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Cited by 197Mitochondrial Function and PathologyMuscle Physiology and DisordersAdipose Tissue and Metabolism

The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass

Open access
Romanello, Vanina, Sandri, Marco·2021·Cellular and Molecular Life Sciences
DOI 10.1007/s00018-020-03662-0PMC PMC7904552
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Abstract

The dynamic coordination of processes controlling the quality of the mitochondrial network is crucial to maintain the function of mitochondria in skeletal muscle. Changes of mitochondrial proteolytic system, dynamics (fusion/fission), and mitophagy induce pathways that affect muscle mass and performance. When muscle mass is lost, the risk of disease onset and premature death is dramatically increased. For instance, poor quality of muscles correlates with the onset progression of several age-related disorders such as diabetes, obesity, cancer, and aging sarcopenia. To date, there are no drug therapies to reverse muscle loss, and exercise remains the best approach to improve mitochondrial health and to slow atrophy in several diseases. This review will describe the principal mechanisms that control mitochondrial quality and the pathways that link mitochondrial dysfunction to muscle mass regulation.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes how mitochondrial quality-control pathways—proteostasis, fusion/fission dynamics, and mitophagy—are mechanistically coupled to the regulation of skeletal muscle mass. It argues that dysregulation of any of these interconnected systems triggers catabolic signaling (notably via AMPK–FoxO3, ATF4, and FGF21) that feeds forward to muscle atrophy, while balanced mitochondrial remodeling preserves muscle and whole-body homeostasis.

Key findings

  • Mitochondrial quality control operates through coordinated systems: mitochondrial proteases (LONP1, ClpP, m-AAA, YME1L1, OMA1, PARL), the UPS/MAD pathway (p97/VCP), UPRmt, mitochondrial dynamics (MFN1/2, OPA1 for fusion; DRP1, MFF, MiD49/51 for fission), MDVs, and mitophagy (PINK1/Parkin-dependent and Parkin-independent receptors BNIP3, NIX, FUNDC1, Bcl2-L-13). A Drosophila proteomic study cited found ~70% of mitochondrial protein turnover occurs via non-autophagic processes, with mitophagy accounting for the remaining ~one third.
  • Muscle-specific deletion of fusion proteins causes severe phenotypes: MFN1/MFN2 double knockout mice die within 6–8 weeks with mtDNA depletion and point mutations; OPA1 deletion in adult mice (3–5 months) reduces mtDNA, respiratory complexes/supercomplexes, and membrane potential, causing atrophy, weakness, systemic inflammation, epithelial senescence, and premature death (rescued by FGF21 co-deletion). OPA1 overexpression protects against denervation- and COX15-deletion-induced muscle loss.
  • Fission is also required: DRP1 overexpression activates atrophy via AMPK–FoxO3 and the eIF2α–ATF4–FGF21 axis; DRP1 ablation in adult muscle causes muscle loss with mitophagy impairment, MCU upregulation, calcium overload, ER stress, and FGF21 induction. PUM2-mediated repression of MFF increases with age; PUM2 deletion in old mice raises MFF, enhances fission/mitophagy, and improves mitochondrial function and lifespan.
  • Unbalanced dynamics are more deleterious than simultaneous reduction of both: OPA1/DRP1 double knockout mice show a less severe phenotype than OPA1 knockout alone, with transient FGF21 elevation and rescued lethality. FGF21 is commonly induced across OPA1-null, DRP1-null, and DKO models but with different magnitudes and outcomes (dose-dependent: moderate = adaptive, dramatic = detrimental).

Methods

  • Narrative review; no primary experimental data. Synthesizes mechanistic cell-biology literature and mouse/human genetic models of mitochondrial quality control and muscle atrophy.
  • Covers human disease genetics (CMT2A from MFN2 mutations, DOA from OPA1 mutations, DRP1/MFF/MiD49 mutations, VCP-associated myopathy) and rodent conditional knockout/transgenic models (muscle-specific MFN1/2, OPA1, DRP1, DKO, PUM2, ATG5/7, VPS15, etc.).
  • Includes a summary table (Table 1) comparing signaling and phenotype of muscle-specific Opa1-, Drp1-, and Drp1/Opa1-null mice at early (70 days) and late (365 days) post-deletion.

Limitations

  • The paper is a review and states no formal limitations of its own; it repeatedly notes open questions, e.g., that IMJ molecular composition and function "have to be defined," that the IMM fission machinery players remain largely unidentified, and that MDV biogenesis machinery is unknown.
  • Evident from the text: several mechanistic conclusions rest on in vitro data whose in vivo physiological relevance "needs to be validated" (e.g., p62/optineurin/NDP52 mitophagy receptor data), and some findings are described as controversial (e.g., MARCHV/MITOL effects on DRP1 vary by cell context).
  • Evident from the text: many causal inferences about muscle mass come from constitutive or conditional knockout mouse models with embryonic lethality or early death, which may not fully represent adult physiological remodeling.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s00018-020-03662-0

Cites

246 of 246 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 331 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    By controlling FoxOs and mTOR, AKT is a regulatory node between catabolic and anabolic processes.

    “Therefore, by controlling FoxOs and mTOR, AKT is a regulatory node between catabolic and anabolic processes.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    The mitochondrial muscle reticulum forms a conductive pathway that can rapidly transfer energy from the capillary to the contractile apparatus.

    “The mitochondrial muscle reticulum forms a conductive pathway that can rapidly transfer energy from the oxygen source, the capillary, to the contractile apparatus [24].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Glancy B, Hartnell LM, Malide D et al (2015) Mitochondrial reticulum for cellular energy distribution in muscle. Nature 523:617–620. https://doi.org/10.1038/nature14614 source

      Not checked in the free run.

  • Interpretationnone given

    Dynamic coordination of processes controlling mitochondrial quality is crucial to maintain mitochondrial function in skeletal muscle.

    “The dynamic coordination of processes controlling the quality of the mitochondrial network is crucial to maintain the function of mitochondria in skeletal muscle.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Mitochondria communicate among themselves through intermitochondrial junctions (IMJs) and nanotunnels.

    “In addition to SS and IMF connection, mitochondria also communicate among themselves through intermitochondrial junctions (IMJs) and nanotunnels.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Muscle-specific inhibition of FoxOs protects from cancer cachexia-, fasting-, hindlimb suspension- or denervation-induced atrophy.

    “Muscle-specific inhibition of FoxOs protects from cancer cachexia-, fasting-, hindlimb suspension- or denervation-induced atrophy [16–18].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Milan G, Romanello V, Pescatore F et al (2015) Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy. Nat Commun 6:6670. https://doi.org/10.1038/ncomms7670 source

      Not checked in the free run.

    • cites [17] Judge SM, Wu C-L, Beharry AW et al (2014) Genome-wide identification of FoxO-dependent gene networks in skeletal muscle during C26 cancer cachexia. BMC Cancer 14:997. https://doi.org/10.1186/1471-2407-14-997 source

      Not checked in the free run.

    • cites [18] Brocca L, Toniolo L, Reggiani C et al (2017) FoxO-dependent atrogenes vary among catabolic conditions and play a key role in muscle atrophy induced by hindlimb suspension. J Physiol (Lond) 595:1143–1158. https://doi.org/10.1113/JP273097 source

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    Premisecitation

    Subsarcolemmal mitochondria have a globular shape and are located just beneath the plasma membrane; a fraction surrounds capillaries and nuclei.

    “Subsarcolemmal (SS) mitochondria have a globular shape and are located just beneath the plasma membrane (sarcolemma). A fraction of these surrounds capillaries and nuclei (perivascular and perinuclear mitochondria, respectively) [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Vincent AE, White K, Davey T et al (2019) Quantitative 3D mapping of the human skeletal muscle mitochondrial network. Cell Rep 26:996-1009.e4. https://doi.org/10.1016/j.celrep.2019.01.010 source

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  • May combine two claims.

    Premisenone given

    Two central ATP-dependent proteolytic systems are activated during muscle atrophy: the ubiquitin-proteasome system and the autophagy-lysosome system.

    “Two central ATP-dependent proteolytic systems are activated during muscle atrophy. The ubiquitin–proteasome system degrades predominantly myofibrillar proteins, whereas the autophagy–lysosome system removes dysfunctional organelles, protein aggregates, and unfolded and toxic proteins.”
    Quote in the paperNot a substantial claim

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    Premisenone given

    Mitochondrial function and energy production are generally reduced during muscle wasting.

    “Moreover, mitochondrial function and, thus, energy production are generally reduced during muscle wasting.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    In catabolic conditions, protein degradation exceeds protein synthesis, leading to muscle weakness and atrophy.

    “Conversely, in catabolic conditions, protein degradation exceeds protein synthesis leading to muscle weakness and muscle atrophy.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    BMP pathway is activated in myostatin knockout and is sufficient, when induced, to promote muscle growth and counteract muscle loss after denervation and in the absence of nutrients.

    “BMP pathway is activated in myostatin knockout and is sufficient, when induced, to promote muscle growth and to counteract muscle loss after denervation and in the absence of nutrients [6–8].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] Sartori R, Schirwis E, Blaauw B et al (2013) BMP signaling controls muscle mass. Nat Genet 45:1309–1318. https://doi.org/10.1038/ng.2772 source

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    • cites [7] Winbanks CE, Chen JL, Qian H et al (2013) The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass. J Cell Biol 203:345–357. https://doi.org/10.1083/jcb.201211134 source

      Not checked in the free run.

    • cites [8] Sartori R, Sandri M (2015) Bone and morphogenetic protein signalling and muscle mass. Curr Opin Clin Nutr Metab Care 18:215–220. https://doi.org/10.1097/MCO.0000000000000172 source

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    Induction of BMP signaling activates Smad1/5/8, which with SMAD4 suppresses MUSA1 and activates mTOR-dependent protein synthesis.

    “Induction of BMP signaling activates Smad1/5/8, which, together with SMAD 4, leads to the suppression of the MUSA1 [6] and the activation of mTOR-dependent protein synthesis [7].”
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    • cites [6] Sartori R, Schirwis E, Blaauw B et al (2013) BMP signaling controls muscle mass. Nat Genet 45:1309–1318. https://doi.org/10.1038/ng.2772 source

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    • cites [7] Winbanks CE, Chen JL, Qian H et al (2013) The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass. J Cell Biol 203:345–357. https://doi.org/10.1083/jcb.201211134 source

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    Based on myosin heavy chain expression, mouse muscles contain four major fiber types (slow type 1 and fast 2A, 2X, 2B), while human muscles contain three major fiber types (slow type 1 and fast 2A and 2X).

    “Based on myosin heavy chain (MHC) expression, mouse muscles contain four major fiber types, slow type 1 and fast 2A, 2X and 2B; while human muscles contain three major fiber types, slow type 1 and fast 2A and 2X [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Schiaffino S, Reggiani C (2011) Fiber types in mammalian skeletal muscles. Physiol Rev 91:1447–1531. https://doi.org/10.1152/physrev.00031.2010 source

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    Premisecitation

    Intermyofibrillar mitochondria are elongated with a tubular shape and are inserted among myofibrils arranged in pairs at the z-line of each sarcomere.

    “The intermyofibrillar (IMF) mitochondria are elongated with a tubular shape [21] and are inserted among myofibrils arranged in pairs at the z-line of each sarcomere [22].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Vincent AE, White K, Davey T et al (2019) Quantitative 3D mapping of the human skeletal muscle mitochondrial network. Cell Rep 26:996-1009.e4. https://doi.org/10.1016/j.celrep.2019.01.010 source

      Not checked in the free run.

    • cites [22] Vendelin M, Béraud N, Guerrero K et al (2005) Mitochondrial regular arrangement in muscle cells: a “crystal-like” pattern. Am J Physiol, Cell Physiol 288:C757-767. https://doi.org/10.1152/ajpcell.00281.2004 source

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    Premisecitation

    The IGF1-AKT-mTOR axis increases protein synthesis by stimulating the translational machinery and simultaneously blocks FoxO transcription factors and protein degradation.

    “The IGF1–AKT-–mTOR axis increases protein synthesis by stimulating the translational machinery and simultaneously blocks FoxOs transcription factors and protein degradation [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Sandri M, Sandri C, Gilbert A et al (2004) Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117:399–412. https://doi.org/10.1016/s0092-8674(04)00400-3 source

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    Premisecitation

    IMJs are detached in dysfunctional mitochondria, promoting electrical isolation and further segregation of the malfunctioning organelle from the network.

    “To prevent the spread of dysfunction, IMJs are detached in dysfunctional mitochondria, promoting the electrical isolation and further segregation from the network of the malfunctioning organelle [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Glancy B, Hartnell LM, Combs CA et al (2017) Power grid protection of the muscle mitochondrial reticulum. Cell Rep 19:487–496. https://doi.org/10.1016/j.celrep.2017.03.063 source

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    Premisenone given

    Muscle mass in adulthood is defined by the dynamic balance between protein synthesis and protein degradation.

    “The muscle mass in adulthood is defined by the dynamic balance between protein synthesis and protein degradation.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    BMP signaling is a positive regulator of muscle mass and is dominant over the myostatin pathway.

    “On the other hand, BMP signaling is a positive regulator of muscle mass and is dominant over the myostatin pathway [6, 7].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Sartori R, Schirwis E, Blaauw B et al (2013) BMP signaling controls muscle mass. Nat Genet 45:1309–1318. https://doi.org/10.1038/ng.2772 source

      Not checked in the free run.

    • cites [7] Winbanks CE, Chen JL, Qian H et al (2013) The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass. J Cell Biol 203:345–357. https://doi.org/10.1083/jcb.201211134 source

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    Premisecitation

    IMJs are highly specific and regulated electron-dense structures defined by close contact of the inner and outer mitochondrial membrane.

    “IMJs are highly specific and regulated electron-dense structures, defined by the close contact of the inner and outer mitochondrial membrane.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Muscles that generate high-intensity activity for short periods have a high representation of fast glycolytic fibers with poor mitochondrial content, decreased reliance on OXPHOS, and fatigability.

    “Instead, muscles that generate a high-intensity activity for short periods (e.g., jumping, kicking), have a high representation of fast glycolytic fibers, which have poor mitochondrial content, decreased reliance on OXPHOS and are fatigable.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Skeletal muscles are composed of specialized fiber types differing in mitochondrial content, metabolic properties, and myosin composition.

    “Skeletal muscles are composed of specialized fiber types which differ in their mitochondrial content, metabolic properties, and myosin composition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Maintaining a functional mitochondrial network in skeletal muscle is fundamental to sustain the metabolic demands imposed by contraction and regulates fuel utilization, energy expenditure, and general metabolism.

    “Therefore, maintaining a functional mitochondrial network in this tissue is fundamental to sustain the metabolic demands imposed by contraction, ultimately regulating fuel utilization, energy expenditure, and general metabolism.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Recent high-resolution 3D microscopy findings challenged the existence of two separated mitochondrial pools and strengthened the concept of a physically and functionally highly interconnected mitochondrial network in skeletal muscle.

    “Recent findings on high-resolution three-dimensional microscopy challenged the existence of two separated mitochondrial pools and strengthened the concept of a physically and functionally highly interconnected mitochondrial network in skeletal muscle [21, 24, 26].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [21] Vincent AE, White K, Davey T et al (2019) Quantitative 3D mapping of the human skeletal muscle mitochondrial network. Cell Rep 26:996-1009.e4. https://doi.org/10.1016/j.celrep.2019.01.010 source

      Not checked in the free run.

    • cites [24] Glancy B, Hartnell LM, Malide D et al (2015) Mitochondrial reticulum for cellular energy distribution in muscle. Nature 523:617–620. https://doi.org/10.1038/nature14614 source

      Not checked in the free run.

    • cites [26] Dahl R, Larsen S, Dohlmann TL et al (2015) Three-dimensional reconstruction of the human skeletal muscle mitochondrial network as a tool to assess mitochondrial content and structural organization. Acta Physiol 213:145–155. https://doi.org/10.1111/apha.12289 source

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    Premisecitation

    Maintaining a healthy skeletal muscle mass is associated with a lower risk of mortality.

    “Instead, maintaining a healthy skeletal muscle mass is associated with a lower risk of mortality [1, 2]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Srikanthan P, Karlamangla AS (2014) Muscle mass index as a predictor of longevity in older adults. Am J Med 127:547–553. https://doi.org/10.1016/j.amjmed.2014.02.007 source

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    • cites [2] Newman AB, Kupelian V, Visser M et al (2006) Strength, but not muscle mass, is associated with mortality in the health, aging and body composition study cohort. J Gerontol A Biol Sci Med Sci 61:72–77. https://doi.org/10.1093/gerona/61.1.72 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The ubiquitin-proteasome system degrades predominantly myofibrillar proteins, whereas the autophagy-lysosome system removes dysfunctional organelles, protein aggregates, and unfolded and toxic proteins.

    “The ubiquitin–proteasome system degrades predominantly myofibrillar proteins, whereas the autophagy–lysosome system removes dysfunctional organelles, protein aggregates, and unfolded and toxic proteins.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Nanotunnels are conserved OMM and IMM double-membrane projections connecting two non-adjacent mitochondria, particularly under pathological conditions.

    “Nanotunnels are conserved OMM and IMM double-membrane projections, connecting two non-adjacent mitochondria [29], particularly under pathological conditions [21].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Vincent AE, Turnbull DM, Eisner V et al (2017) Mitochondrial nanotunnels. Trends Cell Biol 27:787–799. https://doi.org/10.1016/j.tcb.2017.08.009 source

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    • cites [21] Vincent AE, White K, Davey T et al (2019) Quantitative 3D mapping of the human skeletal muscle mitochondrial network. Cell Rep 26:996-1009.e4. https://doi.org/10.1016/j.celrep.2019.01.010 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The main pathways controlling muscle size are IGF1-AKT-mTOR-FoxO and TGFβ/myostatin/BMP signaling.

    “The main pathways controlling muscle size are IGF1–AKT–mTOR–FoxO and TGFβ/myostatin/BMP signaling.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    MFN2, but not MFN1, is expressed on mitochondria-associated endoplasmic reticulum membranes (MAM) and to a lesser extent on ER/SR.

    “MFN2, and not MFN1, is expressed on the mitochondria-associated endoplasmic reticulum membranes (MAM) and, to a lesser extent, to the endoplasmic/sarcoplasmic reticulum (ER/SR) [63, 64].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [63] de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610. https://doi.org/10.1038/nature07534 source

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    • cites [64] Naon D, Zaninello M, Giacomello M et al (2016) Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether. Proc Natl Acad Sci USA 113:11249–11254. https://doi.org/10.1073/pnas.1606786113 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Mitochondria are continuously challenged by reactive oxygen species (ROS), an inexorable by-product of oxidative phosphorylation.

    “Mitochondria are continuously challenged by reactive oxygen species (ROS), an inexorable by-product of oxidative phosphorylation.”
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    Premisereasoning

    Activation of UPRmt improves protein folding, inhibits protein synthesis to alleviate ER stress, and removes damaged proteins.

    “This pathway's activation improves protein folding, inhibits protein synthesis to alleviate ER stress, and removes damaged proteins.”
    Quote in the paperNot a substantial claim

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    Premisereasoning

    MFN1 and MFN2 have a high degree of homology but do not have the same functions.

    “MFN1 and MFN2 have a high degree of homology, but they do not have the same functions.”
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    Interpretationcitation

    MFN1 has greater GTPase membrane tethering activity than MFN2, explaining why MFN1 loss causes more fragmentation.

    “This difference can be explained because MFN1 has a greater GTPase membrane tethering activity [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Ishihara N, Eura Y, Mihara K (2004) Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. J Cell Sci 117:6535–6546. https://doi.org/10.1242/jcs.01565 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Mammalian cells contain several mitochondria quality control systems to preserve organelle homeostasis.

    “Mammalian cells contain several mitochondria quality control systems to preserve the organelle homeostasis.”
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    Premisereasoning

    Mitochondrial homeostasis is ensured by coordination of mitochondrial biogenesis, mitochondrial dynamics, and degradative pathways like mitochondrial proteases, mitochondrial-derived vesicles, and mitophagy.

    “Mitochondrial homeostasis is ensured by the coordination of pathways like mitochondrial biogenesis, mitochondrial dynamics, and degradative pathways like the activation of mitochondrial proteases, mitochondrial-derived vesicles, and mitophagy, the selective degradation of mitochondria via autophagy (Fig. 1).”
    Quote in the paperNot a substantial claim

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    Premisenone given

    In glycolytic fibers, the mitochondrial network is fragmented and perpendicularly oriented to the muscle contraction axis and the I bands.

    “In contrast, the mitochondrial network in glycolytic fibers is fragmented and perpendicularly oriented to the muscle contraction axis and the I bands.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Under stress conditions, when degradation pathways are insufficient, a retrograde signal is activated that coordinates nuclear gene expression; this is the mitochondrial unfolded protein response (UPRmt).

    “Under stress conditions, when the degradation pathways are insufficient to repair the consequences of the alteration in mitochondrial translation [52] or the accumulation of oxidatively damaged or misfolded proteins, a retrograde signal is activated which coordinates nuclear gene expression. This mitochondria-to- nucleus response is named mitochondrial unfolding protein response (UPRmt) [53].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Callegari S, Dennerlein S (2018) Sensing the stress: a role for the UPRmt and UPRam in the quality control of mitochondria. Front Cell Dev Biol 6:31. https://doi.org/10.3389/fcell.2018.00031 source

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    • cites [53] Zhao Q, Wang J, Levichkin IV et al (2002) A mitochondrial specific stress response in mammalian cells. EMBO J 21:4411–4419. https://doi.org/10.1093/emboj/cdf445 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    In mammals, mitochondrial fusion is independently regulated at the OMM and IMM.

    “In mammals, mitochondrial fusion is independently regulated at the OMM and the IMM.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Mitochondrial integrity and function need to be highly regulated.

    “Thus, mitochondrial integrity and function need to be highly regulated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The mitochondrial matrix protein OSCP can be retrotranslocated to the OMM, where it can be ubiquitinated and degraded.

    “For example, the mitochondrial matrix protein OSCP, a subunit of OXPHOS complex V, can be retrotranslocated to the OMM, where it can be ubiquitinated and degraded [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Margineantu DH, Emerson CB, Diaz D, Hockenbery DM (2007) Hsp90 inhibition decreases mitochondrial protein turnover. PLoS ONE 2:e1066. https://doi.org/10.1371/journal.pone.0001066 source

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  • May combine two claims.

    Premisereasoning

    Mitoproteases monitor mitochondrial protein quality and can decide mitochondrial fate.

    “Mitoproteases do not only monitor mitochondrial protein quality, but also they can decide mitochondrial fate.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Mitochondria have an ERAD-like mechanism, the mitochondria-associated degradation (MAD) pathway, and share key components with ERAD.

    “Mitochondria have an ERAD-like mechanism, the mitochondria-associated degradation (MAD) pathway, and share with ERAD some key components.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Only 13 proteins among approximately 1200 proteins of the mitochondrial proteome are encoded by mitochondrial DNA and synthesized inside the organelle.

    “However, only 13 proteins among the approximately 1200 proteins from the mitochondrial proteome, are encoded by mitochondrial DNA (mtDNA) and synthesized inside the organelle [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Calvo SE, Clauser KR, Mootha VK (2016) MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res 44:D1251-1257. https://doi.org/10.1093/nar/gkv1003 source

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    Premisenone given

    Mitochondrial dysfunction is linked to several human diseases, including specific genetic defects, neurodegenerative and age-related diseases like aging sarcopenia, diabetes, and obesity.

    “Mitochondrial dysfunction has been linked to several human diseases, like specific genetic defects, neurodegenerative and age-related diseases like aging sarcopenia, diabetes, and obesity.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Mitochondrial fusion enables redistribution of energy in the form of mitochondrial potential, metabolites, proteins, and mtDNA, improving calcium handling and ATP synthesis.

    “This process enables the redistribution of energy in the form of mitochondrial potential, metabolites, proteins, and mtDNA, improving calcium handling, and ATP synthesis [24, 54–57].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [24] Glancy B, Hartnell LM, Malide D et al (2015) Mitochondrial reticulum for cellular energy distribution in muscle. Nature 523:617–620. https://doi.org/10.1038/nature14614 source

      Not checked in the free run.

    • cites [54] Eisner V, Lenaers G, Hajnóczky G (2014) Mitochondrial fusion is frequent in skeletal muscle and supports excitation-contraction coupling. J Cell Biol 205:179–195. https://doi.org/10.1083/jcb.201312066 source

      Not checked in the free run.

    • cites [55] Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13:589–598. https://doi.org/10.1038/ncb2220 source

      Not checked in the free run.

    • cites [56] Skulachev VP (2001) Mitochondrial filaments and clusters as intracellular power-transmitting cables. Trends Biochem Sci 26:23–29. https://doi.org/10.1016/s0968-0004(00)01735-7 source

      Not checked in the free run.

    • cites [57] Ono T, Isobe K, Nakada K, Hayashi JI (2001) Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria. Nat Genet 28:272–275. https://doi.org/10.1038/90116 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    In the mitochondrial matrix, protein turnover is controlled by three AAA proteases: soluble LONP1 and ClpP and membrane-bound m-AAA.

    “In the mitochondrial matrix, protein turnover is controlled by 3 AAA proteases: the soluble LONP1 and ClpP and the membrane-bound m-AAA.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    According to the degree of mitochondrial damage, different pathways can be activated, ranging from segmental repair to whole degradation of the dysfunctional organelle.

    “According to the degree of mitochondrial damage, different pathways can be activated, ranging from the segmental repair of the damage to the whole degradation of the dysfunctional organelle.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Fusion between healthy and damaged organelles allows dilution of damaged material into the healthy network, avoids accumulation of dysfunctional mitochondria, and maintains overall function.

    “Besides, the fusion between healthy and damaged organelles allows to dilute the damaged material into the healthy network, avoids the accumulation of dysfunctional mitochondria, and maintains their overall function [58].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Twig G, Elorza A, Molina AJA et al (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446. https://doi.org/10.1038/sj.emboj.7601963 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Incorporation of mitochondrial protein precursors into specific subcompartments requires specific and highly regulated import machinery.

    “The incorporation of these precursors into specific mitochondria subcompartments such as the outer mitochondrial membrane (OMM), the intermembrane space (IMS), the inner mitochondrial membrane (IMM) and the mitochondrial matrix requires specific and highly regulated import machinery [35].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Grevel A, Pfanner N, Becker T (2019) Coupling of import and assembly pathways in mitochondrial protein biogenesis. Biol Chem 401:117–129. https://doi.org/10.1515/hsz-2019-0310 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    The nuclear genome encodes the remaining mitochondrial proteins, which are synthesized by ribosomes in precursor forms.

    “The nuclear genome encodes the remaining proteins, which are synthesized by ribosomes in precursor forms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    MFN2 bridges mitochondria to ER/SR, facilitating processes linked to ER-mitochondria interactions like calcium homeostasis and modulation of the UPR during ER stress via PERK.

    “Indeed, MFN2 bridges mitochondria to ER/SR, facilitating critical processes linked to ER–mitochondria interactions like calcium homeostasis and the modulation of the UPR during ER stress via PERK [63, 65–68].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [63] de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610. https://doi.org/10.1038/nature07534 source

      Not checked in the free run.

    • cites [65] Muñoz JP, Ivanova S, Sánchez-Wandelmer J et al (2013) Mfn2 modulates the UPR and mitochondrial function via repression of PERK. EMBO J 32:2348–2361. https://doi.org/10.1038/emboj.2013.168 source

      Not checked in the free run.

    • cites [66] Ngoh GA, Papanicolaou KN, Walsh K (2012) Loss of mitofusin 2 promotes endoplasmic reticulum stress. J Biol Chem 287:20321–20332. https://doi.org/10.1074/jbc.M112.359174 source

      Not checked in the free run.

    • cites [67] Sebastián D, Hernández-Alvarez MI, Segalés J et al (2012) Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. Proc Natl Acad Sci USA 109:5523–5528. https://doi.org/10.1073/pnas.1108220109 source

      Not checked in the free run.

    • cites [68] Ainbinder A, Boncompagni S, Protasi F, Dirksen RT (2015) Role of Mitofusin-2 in mitochondrial localization and calcium uptake in skeletal muscle. Cell Calcium 57:14–24. https://doi.org/10.1016/j.ceca.2014.11.002 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial fusion leads to elongated organelles, which expand the mitochondrial network and its interconnectivity.

    “Mitochondrial fusion leads to elongated organelles, which expand the mitochondrial network and its interconnectivity [32].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Bleck CKE, Kim Y, Willingham TB, Glancy B (2018) Subcellular connectomic analyses of energy networks in striated muscle. Nat Commun 9:5111. https://doi.org/10.1038/s41467-018-07676-y source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Mitochondrial fusion starts with tethering of two adjacent mitochondria, continues with OMM fusion, and concludes with IMM fusion.

    “It starts with the tethering of two adjacent mitochondria, continues with the fusion of OMM, and concludes with IMM fusion.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mitochondria have their own genome, transcription, and translation machinery.

    “Mitochondria have their genome, transcription, and translation machinery [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Lightowlers RN, Rozanska A, Chrzanowska-Lightowlers ZM (2014) Mitochondrial protein synthesis: figuring the fundamentals, complexities and complications, of mammalian mitochondrial translation. FEBS Lett 588:2496–2503. https://doi.org/10.1016/j.febslet.2014.05.054 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Fission separates dysfunctional or damaged components from the network, and the resulting unconnected shorter mitochondria are further removed via mitophagy.

    “On the contrary, fission separates the dysfunctional or damaged components from the network. The resulting unconnected shorter mitochondria will be further removed via mitophagy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    During ER stress, misfolded proteins accumulate in the ER lumen and are retrotranslocated into the cytosol, ubiquitinated, and degraded by the proteasome in ER-associated protein degradation (ERAD).

    “During ER stress, misfolded proteins accumulate into the ER lumen. They need to be retrotranslocated into the cytosol, where they are flagged with ubiquitin and degraded by the proteasome in a process called ER-associated protein degradation (ERAD) [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Ye Y, Meyer HH, Rapoport TA (2001) The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414:652–656. https://doi.org/10.1038/414652a source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Unfolded IMS proteins can exit the IMS through the TOM translocase.

    “Moreover, unfolded IMS proteins can exit the IMS through the TOM translocase, which is the same route used for import [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Bragoszewski P, Gornicka A, Sztolsztener ME, Chacinska A (2013) The ubiquitin-proteasome system regulates mitochondrial intermembrane space proteins. Mol Cell Biol 33:2136–2148. https://doi.org/10.1128/MCB.01579-12 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Mitochondrial fission is a multi-step process that depends primarily on the cytosolic GTPase dynamin-related protein 1 (DRP1).

    “Mitochondrial fission is a multi-step process that depends primarily on the cytosolic GTPase dynamin-related protein 1 (DRP1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Although DRP1 can tubulate membranes, it cannot complete membrane scission.

    “Although DRP1 can tubulate the membranes, it cannot complete membrane scission [84].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Yoon Y, Pitts KR, McNiven MA (2001) Mammalian dynamin-like protein DLP1 tubulates membranes. Mol Biol Cell 12:2894–2905. https://doi.org/10.1091/mbc.12.9.2894 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    DRP1 lacks hydrophobic membrane-binding domains, so its recruitment depends on integral OMM proteins that act as receptors/adaptors.

    “DRP1 lacks hydrophobic membrane-binding domains, and so, its recruitment depends on integral OMM proteins that act as receptors/adaptors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Inner membrane constriction occurs at ER-mitochondria contact sites before DRP1 recruitment and is independent of DRP1 action and OMM division.

    “The inner membrane constriction occurs at ER–mitochondria contact sites before DRP1 recruitment and is thus independent of DRP1 action and OMM division [102, 103].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [102] Cho B, Cho HM, Jo Y et al (2017) Constriction of the mitochondrial inner compartment is a priming event for mitochondrial division. Nat Commun 8:15754. https://doi.org/10.1038/ncomms15754 source

      Not checked in the free run.

    • cites [103] Chakrabarti R, Ji W-K, Stan RV et al (2018) INF2-mediated actin polymerization at the ER stimulates mitochondrial calcium uptake, inner membrane constriction, and division. J Cell Biol 217:251–268. https://doi.org/10.1083/jcb.201709111 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPA1-dependent mitochondrial fusion needs Mfn1 and balanced OPA1S and OPA1L forms.

    “OPA1-dependent mitochondrial fusion needs Mfn1 [73] as well as balanced OPA1S and OPA1L forms.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L (2004) OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA 101:15927–15932. https://doi.org/10.1073/pnas.0407043101 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    DRP1 affinity for MFF is higher than for Fis1, suggesting that MFF preferentially functions as a DRP1 receptor.

    “The DRP1 affinity for MFF is higher than for Fis1, suggesting that MFF preferentially functions as a DRP1 receptor.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mammals lack a homolog of the fission protein FtsZ.

    “However, mammals lack a homolog of the fission protein FtsZ [99].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Leger MM, Petrů M, Žárský V et al (2015) An ancestral bacterial division system is widespread in eukaryotic mitochondria. Proc Natl Acad Sci USA 112:10239–10246. https://doi.org/10.1073/pnas.1421392112 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPA1 controls cristae remodeling and assembly of respiratory chain complexes into supercomplexes, enhancing mitochondrial respiration.

    “OPA1 is a pleiotropic protein that, by forming oligomers of soluble and membrane-bound OPA1 isoforms, also controls cristae remodeling and the assembly of respiratory chain complexes into supercomplexes, a structure that enhances mitochondrial respiration [78].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Cogliati S, Frezza C, Soriano ME et al (2013) Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 155:160–171. https://doi.org/10.1016/j.cell.2013.08.032 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MIEF1/MiD51 and MIEF2/MiD49 recruit DRP1 to mitochondria independent of MFF, but inhibit DRP1 GTPase activity, leading to mitochondrial elongation when overexpressed.

    “MIEF1/MiD51 and the variant MIEF2/MiD49 recruit DRP1 to mitochondria independent of MFF, but in contrast to MFF, inhibit DRP1 GTPase activity leading to mitochondrial elongation when MiD49/51 is overexpressed [92, 95, 96].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [92] Palmer CS, Elgass KD, Parton RG et al (2013) Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and are specific for mitochondrial fission. J Biol Chem 288:27584–27593. https://doi.org/10.1074/jbc.M113.479873 source

      Not checked in the free run.

    • cites [95] Zhao J, Liu T, Jin S et al (2011) Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes mitochondrial fusion rather than fission. EMBO J 30:2762–2778. https://doi.org/10.1038/emboj.2011.198 source

      Not checked in the free run.

    • cites [96] Losón OC, Song Z, Chen H, Chan DC (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24:659–667. https://doi.org/10.1091/mbc.E12-10-0721 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DRP1 is recruited to marked division sites to bind to its OMM receptors/adaptors, facilitating DRP1 oligomerization into a ring-like structure that narrows the membranes.

    “Subsequently, DRP1 is recruited to the marked division sites to bind to its OMM receptors/adaptors. This binding facilitates DRP1 oligomerization, forming a ring-like structure that favors an additional narrowing of the membranes [83].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Kraus F, Ryan MT (2017) The constriction and scission machineries involved in mitochondrial fission. J Cell Sci 130:2953–2960. https://doi.org/10.1242/jcs.199562 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Silencing MFF generates elongated mitochondria and DRP1 cytosolic distribution.

    “On the contrary, silencing MFF generates elongated mitochondria and DRP1 cytosolic distribution [90, 93].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [90] Otera H, Wang C, Cleland MM et al (2010) Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J Cell Biol 191:1141–1158. https://doi.org/10.1083/jcb.201007152 source

      Not checked in the free run.

    • cites [93] Gandre-Babbe S, van der Bliek AM (2008) The novel tail-anchored membrane protein Mff controls mitochondrial and peroxisomal fission in mammalian cells. Mol Biol Cell 19:2402–2412. https://doi.org/10.1091/mbc.e07-12-1287 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under stress conditions, hyperacetylation of OPA1 reduces its GTPase activity, while SIRT3-dependent deacetylation increases OPA1 GTPase activity.

    “Under stress conditions, hyperacetylation of OPA1 reduces its GTPase activity while SIRT3-dependent deacetylation increases OPA1 GTPase activity [79].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Samant SA, Zhang HJ, Hong Z et al (2014) SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol Cell Biol 34:807–819. https://doi.org/10.1128/MCB.01483-13 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ERMD increases in the presence of mtDNA, and mtDNA synthesis is coupled to mitochondrial division to ensure distribution of newly replicated mtDNA to daughter mitochondria.

    “Importantly, ERMD increases in the presence of mtDNA. Thus, mtDNA synthesis is coupled to mitochondrial division to ensure the distribution of newly replicated mtDNA to daughter mitochondria [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Lewis SC, Uchiyama LF, Nunnari J (2016) ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science 353:aff5549. https://doi.org/10.1126/science.aaf5549 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Dynamin 2 (DYN2) assembles in the DRP1-mediated mitochondrial constriction neck to drive mitochondrial scission.

    “Indeed, the GTPase Dynamin 2 (DYN2) assembles in the DRP1-mediated mitochondrial constriction neck to drive mitochondrial scission [85].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Lee JE, Westrate LM, Wu H et al (2016) Multiple dynamin family members collaborate to drive mitochondrial division. Nature 540:139–143. https://doi.org/10.1038/nature20555 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mechanism driving IMM constriction is not elucidated, but the requirement of MCU and OMA1-induced OPA1S has been shown.

    “The mechanism which drives IMM constriction are not elucidated, but the requirement of MCU and OMA1-induced OPA1S has been shown [102, 103].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [102] Cho B, Cho HM, Jo Y et al (2017) Constriction of the mitochondrial inner compartment is a priming event for mitochondrial division. Nat Commun 8:15754. https://doi.org/10.1038/ncomms15754 source

      Not checked in the free run.

    • cites [103] Chakrabarti R, Ji W-K, Stan RV et al (2018) INF2-mediated actin polymerization at the ER stimulates mitochondrial calcium uptake, inner membrane constriction, and division. J Cell Biol 217:251–268. https://doi.org/10.1083/jcb.201709111 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPA1 deletion leads to mitochondrial fragmentation, whereas OPA1 overexpression induces mitochondrial elongation.

    “OPA1 deletion leads to mitochondrial fragmentation, whereas OPA1 overexpression induces mitochondrial elongation [73].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L (2004) OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA 101:15927–15932. https://doi.org/10.1073/pnas.0407043101 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Formation of a Lys63-polyubiquitin chain by the E3 ligase MARCHV/MITOL does not induce MFN2 degradation but increases its activity and MAM formation and function.

    “Conversely, the formation of a Lys63–polyubiquitin chain by the E3 ligase MARCHV/MITOLl does not induce MFN2 degradation but increases its activity and MAM formation and function [71].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Sugiura A, Nagashima S, Tokuyama T et al (2013) MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2. Mol Cell 51:20–34. https://doi.org/10.1016/j.molcel.2013.04.023 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mammals, there are no orthologues for MDV1 and Cav4, and recent evidence suggests that Fis1 is not required for fission.

    “In mammals, there are no orthologues for MDV1 and Cav 4, and recent evidence suggests that Fis1 is not required for fission [89, 90].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [89] Osellame LD, Singh AP, Stroud DA et al (2016) Cooperative and independent roles of the Drp1 adaptors Mff, MiD49 and MiD51 in mitochondrial fission. J Cell Sci 129:2170–2181. https://doi.org/10.1242/jcs.185165 source

      Not checked in the free run.

    • cites [90] Otera H, Wang C, Cleland MM et al (2010) Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J Cell Biol 191:1141–1158. https://doi.org/10.1083/jcb.201007152 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Complete conversion of OPA1L into OPA1S inhibits fusion and increases mitochondrial fission.

    “On the contrary, the complete conversion of OPA1L into OPA1S inhibits fusion and increases mitochondrial fission [74, 76].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [74] Ishihara N, Fujita Y, Oka T, Mihara K (2006) Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO J 25:2966–2977. https://doi.org/10.1038/sj.emboj.7601184 source

      Not checked in the free run.

    • cites [76] Anand R, Wai T, Baker MJ et al (2014) The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J Cell Biol 204:919–929. https://doi.org/10.1083/jcb.201308006 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Mitochondrial division requires division of both the inner and outer mitochondrial membranes.

    “Mitochondrial division requires the division of both the inner and outer mitochondrial membranes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In prokaryotic cells and certain primitive eukaryotic species, FtsZ is a self-assembly GTPase that forms a calcium-mediated constricting ring on the IMM matrix side, suggesting that specific mechanisms for IMM constriction must exist.

    “In prokaryotic cells and certain primitive eukaryotic species, FtsZ is a self-assembly GTPase that forms a calcium-mediated constricting ring on IMM's matrix side, suggesting that specific mechanisms for IMM constriction must exist [98].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Nishida K, Takahara M, Miyagishima S et al (2003) Dynamic recruitment of dynamin for final mitochondrial severance in a primitive red alga. Proc Natl Acad Sci USA 100:2146–2151. https://doi.org/10.1073/pnas.0436886100 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Full knockout mice of either Mfn1, Mfn2, or OPA1 result in embryonic lethality, demonstrating the biological importance of mitochondrial fusion in early development.

    “The full knockout mice of either Mfn1, Mfn2, or OPA1 result in embryonic lethality of mice, demonstrating the biological importance of mitochondrial fusion in early development [60, 178].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Chen H, Detmer SA, Ewald AJ et al (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160:189–200. https://doi.org/10.1083/jcb.200211046 source

      Not checked in the free run.

    • cites [178] Davies VJ, Hollins AJ, Piechota MJ et al (2007) Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function. Hum Mol Genet 16:1307–1318. https://doi.org/10.1093/hmg/ddm079 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The central role of mitochondria in skeletal muscle homeostasis depends not only on energy production, but also on buffering intracellular calcium and on signaling pathways that control nuclear gene programs regulating muscle mass.

    “The central role of mitochondria in skeletal muscle homeostasis depends not only on energy production, but also on the buffering of intracellular calcium, and the signaling pathways that control nuclear gene programs which regulate muscle mass.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Germline deletion of OMA1 does not impair embryogenesis, indicating that OMA1-induced OPA1 processing is dispensable for embryonic and adult mouse development.

    “In contrast to Yme1L1, the germline deletion of OMA1 does not impair embryogenesis, which indicates that OMA1-induced OPA1 processing is dispensable for embryonic and adult mouse development [166, 167].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [166] Wai T, García-Prieto J, Baker MJ et al (2015) Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science 350:aad0116. https://doi.org/10.1126/science.aad0116 source

      Not checked in the free run.

    • cites [167] Quirós PM, Ramsay AJ, Sala D et al (2012) Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice. EMBO J 31:2117–2133. https://doi.org/10.1038/emboj.2012.70 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p97/VCP deficiency results in accumulation of numerous vesicular bodies, autophagy impairment, and altered myofibrillar organization, causing a severe myopathy.

    “Moreover, p97/VCP deficiency resulted in the accumulation of numerous vesicular bodies, autophagy impairment, and altered myofibrillar organization, causing a severe myopathy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [175] Kustermann M, Manta L, Paone C et al (2018) Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo. Autophagy 14:1911–1927. https://doi.org/10.1080/15548627.2018.1491491 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cardiac function and lifespan of mice lacking YME1L in cardiomyocytes are normalized without restoring mitochondrial morphology when deletion of YME1L happens in both cardiomyocytes and skeletal muscle fibers, with median life span 125 weeks.

    “Interestingly, cardiac function and lifespan of mice lacking YME1L in cardiomyocytes are normalized without restoring mitochondrial morphology, when the deletion of YME1L happens in both cardiomyocytes and skeletal muscle fibers (median life span 125 weeks).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Wai T, García-Prieto J, Baker MJ et al (2015) Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science 350:aad0116. https://doi.org/10.1126/science.aad0116 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss-of-function mutations in MFN2 and OPA1 genes cause Charcot-Marie-Tooth type 2A (CMT2A) and dominant optic atrophy (DOA), respectively.

    “Loss-of-function mutations in MFN2 and OPA1 genes cause two neurodegenerative diseases, Charcot–Marie–Tooth type 2A (CMT2A) [179] and dominant optic atrophy (DOA) [180, 181], respectively.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [179] Züchner S, Mersiyanova IV, Muglia M et al (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36:449–451. https://doi.org/10.1038/ng1341 source

      Not checked in the free run.

    • cites [180] Alexander C, Votruba M, Pesch UE et al (2000) OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 26:211–215. https://doi.org/10.1038/79944 source

      Not checked in the free run.

    • cites [181] Delettre C, Lenaers G, Griffoin JM et al (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 26:207–210. https://doi.org/10.1038/79936 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p97/VCP is critical in the retrotranslocation and degradation of endoplasmic reticulum-associated proteins (ERAD) and mitochondrial proteins (MAD).

    “p97/VCP is critical in the retrotranslocation and degradation of endoplasmic reticulum-associated proteins (ERAD) [47] and mitochondrial proteins ( MAD) [49, 50].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [47] Ye Y, Meyer HH, Rapoport TA (2001) The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414:652–656. https://doi.org/10.1038/414652a source

      Not checked in the free run.

    • cites [49] Tanaka A, Cleland MM, Xu S et al (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 191:1367–1380. https://doi.org/10.1083/jcb.201007013 source

      Not checked in the free run.

    • cites [50] Xu S, Peng G, Wang Y et al (2011) The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover. Mol Biol Cell 22:291–300. https://doi.org/10.1091/mbc.E10-09-0748 source

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  • May combine two claims.

    Premisecitation

    Mitochondrial fusion in skeletal muscle is necessary to adapt to the cell's specific functional needs and support skeletal muscle myofiber contractile function.

    “mitochondrial fusion in skeletal muscle is necessary to adapt to the cell's specific functional needs and support skeletal muscle myofibers contractile function [54].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Eisner V, Lenaers G, Hajnóczky G (2014) Mitochondrial fusion is frequent in skeletal muscle and supports excitation-contraction coupling. J Cell Biol 205:179–195. https://doi.org/10.1083/jcb.201312066 source

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    Premisecitation

    In mice, muscle knockdown of PARL results in alteration in mitochondrial cristae morphology, mitochondrial dysfunction, oxidative stress, and altered insulin signaling, probably explained by reduction in PARL-mediated OPA1 processing.

    “In mice, muscle knockdown of PARL results in an alteration in mitochondrial cristae morphology, mitochondrial dysfunction, oxidative stress, and altered insulin signaling, which probably can be explained by the reduction in PARL-mediated OPA1 processing [168].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168] Civitarese AE, MacLean PS, Carling S et al (2010) Regulation of skeletal muscle oxidative capacity and insulin signaling by the mitochondrial rhomboid protease PARL. Cell Metab 11:412–426. https://doi.org/10.1016/j.cmet.2010.04.004 source

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  • May combine two claims.

    Premisecitation

    Double deletion of Yme1L1 and OMA1 specifically in the heart restored mitochondrial morphology and rescued cardiac function.

    “In agreement, double deletion of Yme1L1 and OMA1, specifically in the heart, restored mitochondrial morphology and rescued cardiac function [166].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Wai T, García-Prieto J, Baker MJ et al (2015) Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science 350:aad0116. https://doi.org/10.1126/science.aad0116 source

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    Premisecitation

    Mutations in p97 in mice and humans cause mitochondrial swelling, cristae disruption, oxidative stress, and decreased ATP, resulting in skeletal muscle atrophy and weakness.

    “Mutations in p97 in mice [173] and humans [174] cause mitochondrial swelling, cristae disruption, oxidative stress, and decreased ATP, resulting in skeletal muscle atrophy and weakness.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [173] Nalbandian A, Llewellyn KJ, Kitazawa M et al (2012) The homozygote VCPR155H/R155H mouse model exhibits accelerated human VCP-associated disease pathology. PLoS ONE 7:e46308. https://doi.org/10.1371/journal.pone.0046308 source

      Not checked in the free run.

    • cites [174] Bartolome F, Wu H-C, Burchell VS et al (2013) Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels. Neuron 78:57–64. https://doi.org/10.1016/j.neuron.2013.02.028 source

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  • May combine two claims.

    Premisecitation

    Specific inhibition of Yme1L1 in the heart causes dilated cardiomyopathy that shortens lifespan, with median life span 46 weeks.

    “In mice, total genetic ablation of Yme1L1 leads to embryonic death, while the specific inhibition of the gene in the heart causes dilated cardiomyopathy that shortens lifespan (median life span:46 weeks).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Wai T, García-Prieto J, Baker MJ et al (2015) Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science 350:aad0116. https://doi.org/10.1126/science.aad0116 source

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  • May combine two claims.

    Premisecitation

    YME1L ablation in cardiomyocytes activates OMA1 and promotes OPA1 processing and mitochondrial fragmentation, causing heart failure.

    “Mechanistically, YME1L ablation in cardiomyocytes activates OMA1 and promotes OPA1 processing and mitochondrial fragmentation, which causes heart failure [166].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Wai T, García-Prieto J, Baker MJ et al (2015) Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science 350:aad0116. https://doi.org/10.1126/science.aad0116 source

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    Premisecitation

    In human skeletal muscle, reduction of LonP1 activity results in electron-dense intra-mitochondrial accumulations, mitochondrial dysfunction, oxidative stress, and muscle weakness.

    “In human skeletal muscle, the reduction of LonP1 activity results in electron-dense intra-mitochondrial accumulations, mitochondrial dysfunction, oxidative stress, and muscle weakness [162–164].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [162] Peter B, Waddington CL, Oláhová M et al (2018) Defective mitochondrial protease LonP1 can cause classical mitochondrial disease. Hum Mol Genet 27:1743–1753. https://doi.org/10.1093/hmg/ddy080 source

      Not checked in the free run.

    • cites [163] Hannah-Shmouni F, MacNeil L, Brady L et al (2019) Expanding the clinical spectrum of LONP1-related mitochondrial cytopathy. Front Neurol 10:981. https://doi.org/10.3389/fneur.2019.00981 source

      Not checked in the free run.

    • cites [164] Nimmo GAM, Venkatesh S, Pandey AK et al (2019) Bi-allelic mutations of LONP1 encoding the mitochondrial LonP1 protease cause pyruvate dehydrogenase deficiency and profound neurodegeneration with progressive cerebellar atrophy. Hum Mol Genet 28:290–306. https://doi.org/10.1093/hmg/ddy351 source

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  • May combine two claims.

    Premisecitation

    OMA1-deficient mice display a diet-induced obesity phenotype, increased hepatic steatosis, altered glucose metabolism, and defective thermogenesis, suggesting a role for OMA1 in energy metabolism.

    “OMA1-deficient mice display a diet-induced obesity phenotype, with increased hepatic steatosis and alteration of glucose metabolism, in addition to defective thermogenesis, suggesting a role for OMA1 in energy metabolism [167].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Quirós PM, Ramsay AJ, Sala D et al (2012) Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice. EMBO J 31:2117–2133. https://doi.org/10.1038/emboj.2012.70 source

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  • May combine two claims.

    Premisecitation

    Knockout mice with muscle-specific simultaneous ablation of MFN1 and MFN2 are viable at birth but display muscle growth defects characterized by mitochondrial dysfunction, reduction of mtDNA in skeletal muscle, and accumulation of point mutations and deletions in the mitochondrial genome that cause death within 6-8 weeks of age.

    “Knockout mice are viable at birth, but they display muscle growth defects characterized by mitochondrial dysfunction, reduction of mitochondrial DNA (mtDNA) in skeletal muscle, and accumulation of point mutations deletions in the mitochondrial genome that cause death within 6–8 weeks of age [190].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [190] Chen H, Vermulst M, Wang YE et al (2010) Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 141:280–289. https://doi.org/10.1016/j.cell.2010.02.026 source

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    Premisecitation

    Loss-of-function mutations in MiD49 cause severe myopathy in humans, with Complex I and Complex IV deficiency in muscle.

    “Loss-of-function mutations in MiD49 cause severe myopathy in humans, with Complex I and Complex IV deficiency in muscle [206].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [206] Bartsakoulia M, Pyle A, Troncoso-Chandía D et al (2018) A novel mechanism causing imbalance of mitochondrial fusion and fission in human myopathies. Hum Mol Genet 27:1186–1195. https://doi.org/10.1093/hmg/ddy033 source

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    Premisecitation

    Impairment of fission leads to disruption of selective mitochondrial autophagic degradation, followed by dysfunctional organelle accumulation.

    “Impairment of fission leads to the disruption of selective mitochondrial autophagic degradation, followed by dysfunctional organelles accumulation [58, 196–200].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [58] Twig G, Elorza A, Molina AJA et al (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446. https://doi.org/10.1038/sj.emboj.7601963 source

      Not checked in the free run.

    • cites [196] Favaro G, Romanello V, Varanita T et al (2019) DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass. Nat Commun 10:2576. https://doi.org/10.1038/s41467-019-10226-9 source

      Not checked in the free run.

    • cites [197] Romanello V, Scalabrin M, Albiero M et al (2019) Inhibition of the fission machinery mitigates OPA1 impairment in adult skeletal muscles. Cells. https://doi.org/10.3390/cells8060597 source

      Not checked in the free run.

    • cites [198] Ikeda Y, Shirakabe A, Maejima Y et al (2015) Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ Res 116:264–278. https://doi.org/10.1161/CIRCRESAHA.116.303356 source

      Not checked in the free run.

    • cites [199] Kageyama Y, Hoshijima M, Seo K, et al (2014) Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain. EMBO J 33:2798–2813. https://doi.org/https://doi.org/10.15252/embj.201488658 source

      Not checked in the free run.

    • cites [200] Song M, Mihara K, Chen Y et al (2015) Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab 21:273–286. https://doi.org/10.1016/j.cmet.2014.12.011 source

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  • May combine two claims.

    Premisecitation

    Constitutive DRP1 knockout animals are embryonically lethal, demonstrating that the fission machinery is critical for tissue development and function.

    “Constitutive DRP1 knockout animals are embryonically lethal, demonstrating that the fission machinery is critical for tissue development and function [208, 209].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [208] Ishihara N, Nomura M, Jofuku A et al (2009) Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat Cell Biol 11:958–966. https://doi.org/10.1038/ncb1907 source

      Not checked in the free run.

    • cites [209] Wakabayashi J, Zhang Z, Wakabayashi N et al (2009) The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice. J Cell Biol 186:805–816. https://doi.org/10.1083/jcb.200903065 source

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  • May combine two claims.

    Premisecitation

    In mice, MFF deletion leads to smaller animals that display neuromuscular defects, kyphosis, and premature death at 13 weeks due to dilated cardiomyopathy.

    “In mice, MFF deletion leads to smaller animals that display neuromuscular defects, kyphosis, and premature death at 13 weeks due to dilated cardiomyopathy [207].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [207] Chen H, Ren S, Clish C et al (2015) Titration of mitochondrial fusion rescues Mff-deficient cardiomyopathy. J Cell Biol 211:795–805. https://doi.org/10.1083/jcb.201507035 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPA1 transgenic mice are protected from acute muscle loss induced by denervation and from chronic muscle loss in a model of myopathy caused by muscle-specific deletion of COX15.

    “OPA1 transgenic mice are protected from acute muscle loss induced by denervation [194] as well as from chronic muscle loss in a model of myopathy caused by muscle-specific deletion of the mitochondrial subunit COX15 [195].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [194] Varanita T, Soriano ME, Romanello V et al (2015) The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage. Cell Metab 21:834–844. https://doi.org/10.1016/j.cmet.2015.05.007 source

      Not checked in the free run.

    • cites [195] Civiletto G, Varanita T, Cerutti R et al (2015) Opa1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models. Cell Metab 21:845–854. https://doi.org/10.1016/j.cmet.2015.04.016 source

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  • May combine two claims.

    Premisecitation

    These transcriptional programs enhance ubiquitin-proteasome and autophagy-lysosome protein breakdown, hypoglycemia, lipolysis, liver steatosis, inflammation, and a pro-senescent phenotype.

    “Altogether, these transcriptional-dependent programs enhance ubiquitin–proteasome and autophagy–lysosome protein breakdown, hypoglycemia, lipolysis, liver steatosis, inflammation, and a pro-senescent phenotype.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Tezze C, Romanello V, Desbats MA et al (2017) Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell Metab 25:1374-1389.e6. https://doi.org/10.1016/j.cmet.2017.04.021 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Maintenance of mitochondrial shape and function through fusion events is required to modulate nuclear gene expression programs and muscle mass and to control crosstalk of muscle with distant organs influencing whole-body metabolic homeostasis.

    “Altogether, the maintenance of mitochondrial shape and function, through fusion events, is required not only to modulate nuclear gene expression programs and, thus, muscle mass but also to control the crosstalk of muscle with distant organs influencing the whole-body metabolic homeostasis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    OPA1-deficient muscles cause a systemic inflammatory response, senescence of epithelial tissues, and premature death.

    “Moreover, OPA1-deficient muscles reverberate to the whole body, causing a systemic inflammatory response, senescence of epithelial tissues, and premature death.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Tezze C, Romanello V, Desbats MA et al (2017) Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell Metab 25:1374-1389.e6. https://doi.org/10.1016/j.cmet.2017.04.021 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of OPA1 in adult mice (3-5 months of age) results in a decrease of mtDNA, reduced respiratory complexes and supercomplexes content, and reduced complex activity, respiration, and mitochondrial membrane potential.

    “Deletion of OPA1 in adult mice (3–5 months of age) resulted in a decrease of mtDNA, reduced respiratory complexes and supercomplexes content, and complex activity, respiration, and mitochondrial membrane potential.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [187] Tezze C, Romanello V, Desbats MA et al (2017) Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell Metab 25:1374-1389.e6. https://doi.org/10.1016/j.cmet.2017.04.021 source

      Not checked in the free run.

    • cites [192] Rodríguez-Nuevo A, Díaz-Ramos A, Noguera E et al (2018) Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency. EMBO J. https://doi.org/10.15252/embj.201796553 source

      Not checked in the free run.

    • cites [193] Pereira RO, Tadinada SM, Zasadny FM et al (2017) OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance. EMBO J 36:2126–2145. https://doi.org/10.15252/embj.201696179 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPA1 inhibition causes mitochondrial dysfunction, ROS production, and mitochondrial DNA release that trigger transcription factors FoxO3, NFkB, and ATF4, which coordinate upregulation of atrophy-related genes, FGF21, and inflammatory cytokines like IL6.

    “Mechanistically, OPA1 inhibition causes mitochondrial dysfunction, ROS production, and mitochondrial DNA release that trigger different transcription factors such as FoxO3, NFkB, and ATF4 that coordinate the upregulation of atrophy-related genes, FGF21 and inflammatory cytokines like IL6.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Tezze C, Romanello V, Desbats MA et al (2017) Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell Metab 25:1374-1389.e6. https://doi.org/10.1016/j.cmet.2017.04.021 source

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  • May combine two claims.

    Premisecitation

    Acute OPA1 inhibition in adult animals' skeletal muscles triggers oxidative stress, ER stress, muscle atrophy, and weakness, recapitulating several features of the conditional model.

    “Accordingly, acute OPA1 inhibition in adult animals' skeletal muscles triggers oxidative stress, ER stress, muscle atrophy, and weakness, recapitulating several features of the conditional model [187].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Tezze C, Romanello V, Desbats MA et al (2017) Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell Metab 25:1374-1389.e6. https://doi.org/10.1016/j.cmet.2017.04.021 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FGF21 mediates the pro-aging effects of OPA1 deficiency because deletion of both OPA1 and FGF21 reverts precocious senescence and mortality.

    “FGF21 mediates these pro-aging effects because the deletion of both OPA1 and FGF21 reverts precocious senescence and mortality [187].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Tezze C, Romanello V, Desbats MA et al (2017) Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell Metab 25:1374-1389.e6. https://doi.org/10.1016/j.cmet.2017.04.021 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MFN2 deletion in young muscle causes extensive mitochondrial fragmentation, mitochondrial dysfunction, ROS production, ER stress, and autophagy inhibition resulting in muscle atrophy.

    “MFN2 deletion in young muscle causes extensive mitochondrial fragmentation, mitochondrial dysfunction, ROS production, ER stress, and autophagy inhibition resulting in muscle atrophy [67, 186].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [67] Sebastián D, Hernández-Alvarez MI, Segalés J et al (2012) Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. Proc Natl Acad Sci USA 109:5523–5528. https://doi.org/10.1073/pnas.1108220109 source

      Not checked in the free run.

    • cites [186] Sebastián D, Sorianello E, Segalés J et al (2016) Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway. EMBO J 35:1677–1693. https://doi.org/10.15252/embj.201593084 source

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  • May combine two claims.

    Premisecitation

    Specific deletion of PUM2 in old mice's skeletal muscle increases MFF levels, enhances mitochondrial fission and mitophagy, and improves mitochondrial function and lifespan.

    “Accordingly, the specific deletion of PUM2 in old mice's skeletal muscle increases MFF levels, enhances mitochondrial fission and mitophagy, and improves mitochondrial function and lifespan [119].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] D’Amico D, Mottis A, Potenza F et al (2019) The RNA-binding protein PUM2 impairs mitochondrial dynamics and mitophagy during aging. Mol Cell 73:775-787.e10. https://doi.org/10.1016/j.molcel.2018.11.034 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Muscle-specific OPA1, DRP1, and double OPA1/DRP1 (DKO) knockout mice have common alterations in mitochondrial function, ER stress, and UPS activation but different phenotypes in terms of muscle atrophy, weakness, senescence and animal survival.

    “As stated before, muscle-specific OPA1, DRP1, and the double OPA1/DRP1 (DKO) knockout mice have common alterations in mitochondrial function, ER stress, and UPS activation but different phenotypes in terms of muscle atrophy, weakness, senescence and animal survival (Table 1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    In case of a profound inhibition of either fusion or fission machinery, muscle cells downregulate the other one to mitigate the detrimental effects of an unbalanced mitochondrial dynamics.

    “Therefore, it is possible that in case of a profound inhibition of either fusion or fission machinery, muscle cells downregulate the other one to mitigate the detrimental effects of an unbalanced mitochondrial dynamics.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Under physiological conditions, mitochondrial fusion and fission are balanced to control mitochondrial morphology, size, and number.
    • Rests on an assumption: Excessive activation or impairment of either fusion or fission alters the balance and compromises mitochondrial function and cell health.

  • May combine two claims.

    Premisecitation

    Another study using muscle-specific DRP1 heterozygote mice showed reduced muscle endurance and running performance, and altered muscle adaptations in response to exercise training.

    “Another study using muscle-specific DRP1 heterozygote mice showed reduced muscle endurance and running performance, and altered muscle adaptations in response to exercise training [211].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [211] Moore TM, Zhou Z, Cohn W et al (2019) The impact of exercise on mitochondrial dynamics and the role of Drp1 in exercise performance and training adaptations in skeletal muscle. Mol Metab 21:51–67. https://doi.org/10.1016/j.molmet.2018.11.012 source

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  • May combine two claims.

    Premisecitation

    The atrophy program's initial activation and the induction of FGF21 resolve over time in DKO muscles despite persistent mitochondrial dysfunction.

    “The atrophy program's initial activation and the induction of FGF21 resolve over time in DKO muscles despite persistent mitochondrial dysfunction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197] Romanello V, Scalabrin M, Albiero M et al (2019) Inhibition of the fission machinery mitigates OPA1 impairment in adult skeletal muscles. Cells. https://doi.org/10.3390/cells8060597 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    FGF21 can be both a therapeutic agent and a biomarker of disease.

    “According to the combination of these variables, FGF21 can be both a therapeutic agent and a biomarker of disease [219].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [219] Suomalainen A, Elo JM, Pietiläinen KH et al (2011) FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 10:806–818. https://doi.org/10.1016/S1474-4422(11)70155-7 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DKO mice show muscle loss and weakness due to FoxO-dependent activation of the ubiquitin-proteasome system and general autophagy impairment.

    “DKO showed muscle loss and weakness due to FoxO-dependent activation of the ubiquitin–proteasome system and general autophagy impairment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197] Romanello V, Scalabrin M, Albiero M et al (2019) Inhibition of the fission machinery mitigates OPA1 impairment in adult skeletal muscles. Cells. https://doi.org/10.3390/cells8060597 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Mitochondrial fission is critical for muscle mass maintenance and homeostasis and can be protective or detrimental according to the degree of induction and the physiological context.

    “Thus, mitochondrial fission is critical for muscle mass maintenance and homeostasis and can be protective or detrimental according to the degree of induction and the physiological context.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    FGF21 effects are dose dependent: a moderate induction results in adaptive responses to stress, while a dramatic increase is detrimental.

    “Since FGF21 effects are dose dependent, a moderate induction results in adaptive responses to stress, while a dramatic increase is detrimental [218].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [218] Conte M, Ostan R, Fabbri C et al (2019) Human aging and longevity are characterized by high levels of mitokines. J Gerontol A Biol Sci Med Sci 74:600–607. https://doi.org/10.1093/gerona/gly153 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute ablation of DRP1 in adulthood causes muscle loss and degeneration.

    “Early deletion of DRP1 in skeletal muscle during embryogenesis resulted in reduced postnatal growth and premature lethality, while its acute ablation in adulthood causes muscle loss and degeneration [196].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [196] Favaro G, Romanello V, Varanita T et al (2019) DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass. Nat Commun 10:2576. https://doi.org/10.1038/s41467-019-10226-9 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Specific deletion of MFN1, MFN2, and DRP1 leads to less severe cardiomyopathy and delays mortality with respect to unopposed fission or fusion.

    “For instance, the specific deletion of MFN1, MFN2, and DRP1 leads to less severe cardiomyopathy and delays mortality with respect to unopposed fission or fusion [217].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [217] Song M, Franco A, Fleischer JA et al (2017) Abrogating mitochondrial dynamics in mouse hearts accelerates mitochondrial senescence. Cell Metab 26:872-883.e5. https://doi.org/10.1016/j.cmet.2017.09.023 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PUM2 levels increase with age in worms, mice, and humans, while MFF is reduced upon aging, suggesting that abnormal mitochondrial fission and mitophagy contribute to age-related sarcopenia.

    “PUM2 levels increase with age in worms, mice and humans, while MFF is reduced upon aging, suggesting that abnormal mitochondrial fission and mitophagy contribute to age-related sarcopenia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] D’Amico D, Mottis A, Potenza F et al (2019) The RNA-binding protein PUM2 impairs mitochondrial dynamics and mitophagy during aging. Mol Cell 73:775-787.e10. https://doi.org/10.1016/j.molcel.2018.11.034 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Constitutive overexpression of DRP1 in skeletal muscle causes muscle loss and decreased exercise performance.

    “Accordingly, the constitutive overexpression of DRP1 in skeletal muscle caused muscle loss and decreased exercise performance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [210] Touvier T, De Palma C, Rigamonti E et al (2015) Muscle-specific Drp1 overexpression impairs skeletal muscle growth via translational attenuation. Cell Death Dis 6:e1663. https://doi.org/10.1038/cddis.2014.595 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a DRP1 overexpression mouse model, stress-induced mitochondria-dependent signals activate both the UPRmt and the eIF2α-ATF4-FGF21 axis, causing a reduction in protein synthesis and a blockade of growth hormone actions that prevent muscle growth.

    “In this mouse model, stress-induced mitochondria-dependent signals activate both the UPRmt and the eIF2α–ATF4– FGF21 axis, causing a reduction in protein synthesis and a blockade of growth hormones actions that prevent muscle growth [210].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [210] Touvier T, De Palma C, Rigamonti E et al (2015) Muscle-specific Drp1 overexpression impairs skeletal muscle growth via translational attenuation. Cell Death Dis 6:e1663. https://doi.org/10.1038/cddis.2014.595 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DRP1 inhibition induces autophagy and mitophagy impairment, MCU upregulation, mitochondrial calcium overload, ER stress, UPR activation, and FGF21 induction.

    “Mechanistically, DRP1 inhibition induced autophagy and mitophagy impairment, MCU upregulation and mitochondrial calcium overload, ER stress, UPR activation, and FGF21 induction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [196] Favaro G, Romanello V, Varanita T et al (2019) DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass. Nat Commun 10:2576. https://doi.org/10.1038/s41467-019-10226-9 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In DRP1-null muscles, the sarcoplasmic reticulum's calcium stores are unchanged, while abnormal elongated mitochondria display increased MCU-dependent mitochondrial Ca2+ uptake capacity, leading to myofiber death and muscle regeneration.

    “In DRP1-null muscles, the sarcoplasmic reticulum's calcium stores are unchanged, while abnormal elongated mitochondria display increased MCU-dependent mitochondrial Ca2 + uptake capacity, leading to myofiber death and muscle regeneration [196].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [196] Favaro G, Romanello V, Varanita T et al (2019) DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass. Nat Commun 10:2576. https://doi.org/10.1038/s41467-019-10226-9 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute overexpression of DRP1 is sufficient to activate mitochondrial dysfunction, mitophagy, and energy stress, which result in activation of an atrophy program via the AMPK-FoxO3 axis.

    “Acute overexpression of DRP1 is sufficient to activate mitochondrial dysfunction, mitophagy, and energy stress, which result in the activation of an atrophy program via the AMPK–FoxO3 axis [152].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [152] Romanello V, Guadagnin E, Gomes L et al (2010) Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J 29:1774–1785. https://doi.org/10.1038/emboj.2010.60 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Simultaneous deletion of MFN1 and MFF in mice rescues mitochondrial function, heart dysfunction, and lifespan of both lethal MFN1 and MFF knockout mice.

    “Similarly, the simultaneous deletion of MFN1 and MFF in mice rescues mitochondrial function, heart dysfunction, and lifespan of both lethal MFN1 and MFF knockout mice [207].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [207] Chen H, Ren S, Clish C et al (2015) Titration of mitochondrial fusion rescues Mff-deficient cardiomyopathy. J Cell Biol 211:795–805. https://doi.org/10.1083/jcb.201507035 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle denervation, oxidative stress, and inflammation are mitigated in DKO muscles, rescuing the lethal phenotype of OPA1 knockout mice.

    “Moreover, muscle denervation, oxidative stress, and inflammation are mitigated in DKO muscles, rescuing the lethal phenotype of OPA1 knockout mice [197].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197] Romanello V, Scalabrin M, Albiero M et al (2019) Inhibition of the fission machinery mitigates OPA1 impairment in adult skeletal muscles. Cells. https://doi.org/10.3390/cells8060597 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    As a consequence of mitochondrial dysfunction, ER stress, UPR, and FGF21 pathways are activated and further contribute to muscle atrophy.

    “As a consequence of mitochondrial dysfunction, ER stress, UPR, and FGF21 pathways are activated and further contribute to muscle atrophy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197] Romanello V, Scalabrin M, Albiero M et al (2019) Inhibition of the fission machinery mitigates OPA1 impairment in adult skeletal muscles. Cells. https://doi.org/10.3390/cells8060597 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    FGF21 is commonly induced when mitochondrial function is impaired and dictates healthy or unhealthy skeletal muscle outcomes.

    “Thus, FGF21 is commonly induced when mitochondrial function is impaired and dictates healthy or unhealthy skeletal muscle outcomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Simultaneous inhibition of OPA1 and DRP1 rescues mortality and FGF21 serum levels are only transiently elevated.

    “Consistently, the simultaneous inhibition of OPA1 and DRP1 rescues mortality [197] and FGF21 serum levels are only transiently elevated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197] Romanello V, Scalabrin M, Albiero M et al (2019) Inhibition of the fission machinery mitigates OPA1 impairment in adult skeletal muscles. Cells. https://doi.org/10.3390/cells8060597 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both excessive autophagy and deficient degradation of cytosolic components contribute to muscle atrophy.

    “Both excessive autophagy [140, 186] and the deficient degradation of cytosolic components [225, 226] contribute to muscle atrophy.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [140] Sandoval H, Thiagarajan P, Dasgupta SK et al (2008) Essential role for Nix in autophagic maturation of erythroid cells. Nature 454:232–235. https://doi.org/10.1038/nature07006 source

      Not checked in the free run.

    • cites [186] Sebastián D, Sorianello E, Segalés J et al (2016) Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway. EMBO J 35:1677–1693. https://doi.org/10.15252/embj.201593084 source

      Not checked in the free run.

    • cites [225] Greene JC, Whitworth AJ, Kuo I et al (2003) Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci USA 100:4078–4083. https://doi.org/10.1073/pnas.0737556100 source

      Not checked in the free run.

    • cites [226] Park J, Lee SB, Lee S et al (2006) Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441:1157–1161. https://doi.org/10.1038/nature04788 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The protective effects of autophagy and mitophagy rely on the fine-tuning of the flux; otherwise, it can become detrimental instead of protective.

    “Importantly, the protective effects of autophagy and mitophagy rely on the fine-tuning of the flux; otherwise, it can become detrimental instead of being protective.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Exercise reactivates mitophagy, reduces accumulation of ROS, improves mitochondrial health, and delays the loss of muscle mass that accompanies various pathologies, including aging sarcopenia, heart failure, and neurogenic myopathy.

    “Moreover, exercise is the best non-pharmacological strategy to reactivate mitophagy, which reduces the accumulation of ROS and thus, improves mitochondrial health and delays the loss of muscle mass that accompanies various pathologies, including aging sarcopenia, heart failure and neurogenic myopathy [224, 238–240].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [224] Memme JM, Erlich AT, Phukan G, Hood DA (2019) Exercise and mitochondrial health. J Physiol (Lond). https://doi.org/10.1113/JP278853 source

      Not checked in the free run.

    • cites [238] Campos JC, Baehr LM, Gomes KMS et al (2018) Exercise prevents impaired autophagy and proteostasis in a model of neurogenic myopathy. Sci Rep 8:11818. https://doi.org/10.1038/s41598-018-30365-1 source

      Not checked in the free run.

    • cites [239] Campos JC, Queliconi BB, Bozi LHM et al (2017) Exercise reestablishes autophagic flux and mitochondrial quality control in heart failure. Autophagy 13:1304–1317. https://doi.org/10.1080/15548627.2017.1325062 source

      Not checked in the free run.

    • cites [240] Cunha TF, Bechara LRG, Bacurau AVN et al (2017) Exercise training decreases NADPH oxidase activity and restores skeletal muscle mass in heart failure rats. J Appl Physiol 122:817–827. https://doi.org/10.1152/japplphysiol.00182.2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is an increase in autophagosome formation on mitochondria that cannot fuse with the lysosome, resulting in mitophagy impairment and mitochondrial dysfunction over time.

    “Consequently, there is an increase in autophagosome formation on mitochondria, that however, cannot fuse with the lysosome resulting in mitophagy impairment and mitochondrial dysfunction during the time [229].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [229] Kravic B, Harbauer AB, Romanello V et al (2018) In mammalian skeletal muscle, phosphorylation of TOMM22 by protein kinase CSNK2/CK2 controls mitophagy. Autophagy 14:311–335. https://doi.org/10.1080/15548627.2017.1403716 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Mitochondria are signaling platforms that not only control muscle mass, but also mediate systemically the communication of the muscle with distant tissues influencing whole-body homeostasis.

    “Thus, mitochondria are signaling platforms that not only control muscle mass, but also mediate systemically the communication of the muscle with distant tissues influencing the whole-body homeostasis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Multiple mechanisms have evolved to couple the constant reshaping of the mitochondrial network to the regulation of mitochondrial function, including the activation of proteolytic cascades, mitochondrial fusion, fission, and mitophagy.

    “Multiple mechanisms have evolved to couple the constant reshaping of the mitochondrial network to the regulation of mitochondrial function, including the activation of proteolytic cascades, mitochondrial fusion, and fission mitophagy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Long-term mTORC1 inhibition in muscles results in myopathy, muscle weakness, and alterations in neuromuscular junctions reducing general autophagy and mitophagy.

    “Long-term mTORC1 inhibition in muscles results in myopathy, muscle weakness, and alterations in neuromuscular junctions reducing general autophagy and mitophagy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [235] Baraldo M, Geremia A, Pirazzini M et al (2020) Skeletal muscle mTORC1 regulates neuromuscular junction stability. J Cachexia Sarcopenia Muscle 11:208–225. https://doi.org/10.1002/jcsm.12496 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These mechanisms collectively constitute an interconnected mitochondrial quality control system that recognizes and resolves mitochondrial dysfunction, crucial for skeletal muscle mass maintenance.

    “These mechanisms collectively constitute an interconnected mitochondrial quality control system that recognizes and resolves mitochondrial dysfunction, crucial for skeletal muscle mass maintenance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Skeletal muscle is an endocrine organ that releases myokines in response to mitochondrial stress, such as FGF21, regulating the physiology of the organism and influencing disease progression in other tissues.

    “Moreover, skeletal muscle is an endocrine organ that releases myokines in response to mitochondrial stress, such as FGF21, regulating the physiology of the organism, and influencing disease progression in other tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Impairment of autophagy by muscle-specific ablation of ATG5 and ATG7 induces accumulation of abnormal mitochondria, induction of oxidative stress, apoptosis, muscle atrophy, weakness, and several features of myopathy.

    “Likewise, impairment of autophagy by muscle-specific ablation of ATG5 and ATG7 induces accumulation of abnormal mitochondria, induction of oxidative stress, apoptosis, muscle atrophy, weakness, several features of myopathy [230, 231].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [230] Raben N, Hill V, Shea L et al (2008) Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease. Hum Mol Genet 17:3897–3908. https://doi.org/10.1093/hmg/ddn292 source

      Not checked in the free run.

    • cites [231] Masiero E, Agatea L, Mammucari C et al (2009) Autophagy is required to maintain muscle mass. Cell Metab 10:507–515. https://doi.org/10.1016/j.cmet.2009.10.008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Mitochondria undergo adaptive structural and functional remodeling to meet the dynamic changes in the cell's metabolic demands.

    “Mitochondria undergo adaptive structural and functional remodeling to meet the dynamic changes in the cell's metabolic demands.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Boosting mitophagy by overexpressing PINK1, Parkin, DRP1, or p62 in Drosophila muscles improves age-dependent muscle function deterioration and extends lifespan.

    “Boosting mitophagy by overexpressing PINK1, Parkin, DRP1, or p62 in Drosophila muscles improves the age-dependent muscle function deterioration and extends lifespan [214, 236, 237].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [214] Rana A, Oliveira MP, Khamoui AV et al (2017) Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster. Nat Commun 8:448. https://doi.org/10.1038/s41467-017-00525-4 source

      Not checked in the free run.

    • cites [236] Si H, Ma P, Liang Q et al (2019) Overexpression of pink1 or parkin in indirect flight muscles promotes mitochondrial proteostasis and extends lifespan in Drosophila melanogaster. PLoS ONE. https://doi.org/10.1371/journal.pone.0225214 source

      Not checked in the free run.

    • cites [237] Aparicio R, Rana A, Walker DW (2019) Upregulation of the autophagy adaptor p62/SQSTM1 prolongs health and lifespan in middle-aged drosophila. Cell Rep 28:1029-1040.e5. https://doi.org/10.1016/j.celrep.2019.06.070 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced CK2-mediated TOMM22 phosphorylation weakens the binding between PINK1 and TOMM22, leading to decreased IMM PINK1 import and further OMM PINK1 accumulation.

    “The reduced CK2-mediated TOMM22 phosphorylation weakens the binding between PINK1 and TOMM22, leading to decreased IMM PINK1 import and further OMM PINK1 accumulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [229] Kravic B, Harbauer AB, Romanello V et al (2018) In mammalian skeletal muscle, phosphorylation of TOMM22 by protein kinase CSNK2/CK2 controls mitophagy. Autophagy 14:311–335. https://doi.org/10.1080/15548627.2017.1403716 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute deletion of ATG7 specifically in skeletal muscle does not affect exercise performance, suggesting that autophagy is not required to sustain muscle contraction during exercise training.

    “The acute deletion of ATG7, specifically in skeletal muscle, does not affect exercise performance suggesting that autophagy is not required to sustain muscle contraction during exercise training [222, 223].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [222] Lo Verso F, Carnio S, Vainshtein A, Sandri M (2014) Autophagy is not required to sustain exercise and PRKAA1/AMPK activity but is important to prevent mitochondrial damage during physical activity. Autophagy 10:1883–1894. https://doi.org/10.4161/auto.32154 source

      Not checked in the free run.

    • cites [223] Lira VA, Okutsu M, Zhang M et al (2013) Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance. FASEB J 27:4184–4193. https://doi.org/10.1096/fj.13-228486 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dysregulation of the autophagy flux is detrimental for myofiber health and is a common feature of several myopathies.

    “Dysregulation of the autophagy flux is detrimental for myofiber health and is a common feature of several myopathies [241].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [241] Castets P, Frank S, Sinnreich M, Rüegg MA (2016) “Get the balance right”: pathological significance of autophagy perturbation in neuromuscular disorders. J Neuromuscul Dis 3:127–155. https://doi.org/10.3233/JND-160153 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle-specific ATG7 null mice display premature aging characterized by increased oxidative stress, mitochondrial dysfunction, muscle loss and weakness, and degeneration of neuromuscular junctions.

    “Accordingly, muscle-specific ATG7 null mice display premature aging characterized by increased oxidative stress, mitochondrial dysfunction, muscle loss and weakness, and degeneration of neuromuscular junctions [234].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [234] Carnio S, LoVerso F, Baraibar MA et al (2014) Autophagy impairment in muscle induces neuromuscular junction degeneration and precocious aging. Cell Rep 8:1509–1521. https://doi.org/10.1016/j.celrep.2014.07.061 source

      Not checked in the free run.

138 of 138

  • The paper relies on this without support.

    Mitochondrial dysfunction is linked to muscle function loss in age-related metabolic disorders such as diabetes, obesity, cancer, and aging sarcopenia.

    “Mitochondrial dysfunction has been linked to muscle function loss that occurs in several age-related metabolic disorders such as diabetes, obesity, cancer, and aging sarcopenia.”

  • The paper relies on this without support.

    Loss of muscle mass increases the risk of disease onset and premature death.

    “When muscle mass is lost, the risk of disease onset and premature death is dramatically increased.”

  • The paper relies on this without support.

    Skeletal muscle is a post-mitotic tissue whose cells do not divide, so damaged or dysfunctional mitochondria cannot be diluted through cellular division.

    “Skeletal muscle is a post-mitotic tissue. Its cells do not divide, and consequently, damaged/dysfunctional mitochondria cannot be diluted through cellular division.”

  • The paper relies on this without support.

    Under physiological conditions, mitochondrial fusion and fission are balanced to control mitochondrial morphology, size, and number.

    “Under physiological conditions, fusion and fission processes are balanced to control mitochondrial morphology, size, and number.”

  • The paper relies on this without support.

    Excessive activation or impairment of either fusion or fission alters the balance and compromises mitochondrial function and cell health.

    “However, an excessive activation or the impairment of either fusion or fission alter the balance and compromise mitochondrial function and cell health.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • DRP1 is recruited to marked division sites, binds OMM receptors and adaptors Mff and Fis1, and this binding facilitates DRP1 oligomerization into a ring-like structure that promotes complete mitochondrial division.

    “Subsequently, DRP1 is recruited to these marked division sites, binding to its OMM receptors and adaptors, namely mitochondrial fission factor (Mff) and fission protein 1 (Fis1). This binding event facilitates the oligomerization of DRP1, leading to the formation of a ring-like structure that promotes complete division of the mitochondria [15].”

    From Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds (2024) · cites this paper as [15]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • PUM2 regulation of MFF is described as both transcriptional and translational

    Minor

    One section says PUM2 inhibits MFF transcription, while a later section says it binds MFF mRNA and represses its translation.

  • Reduced fusion is said to produce both elongated and fragmented mitochondria

    Minor

    The Fig. 2 caption says reduced mitochondrial fusion produces elongated mitochondria, whereas the text says deletion of the fusion protein OPA1 produces fragmentation.

  • ClpP and YME1L1 are inconsistently classified as m-AAA proteases

    Minor

    The UPRmt section calls both proteins m-AAA proteases, but the earlier classification distinguishes ClpP from m-AAA and identifies YME1L1 as i-AAA.

3 of 3

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Authors
Romanello, V., & Sandri, M.
Affiliations
University of Padua (IT)
Corresponding author
  • Romanello, Vanina
  • Sandri, Marco
ORCID
Venue
Cellular and Molecular Life Sciences
Publisher
Springer Science and Business Media LLC
Published
2020-10-19
Volume
78
Issue
4
Pages
1305-1328
ISSN
  • 1420-682X (ISSN-L)
  • 1420-9071
DOI
10.1007/s00018-020-03662-0
PMC
PMC7904552
OpenAlex
W3093074122
Semantic Scholar
6cf3598c4058c9e10455aa048d5f3688e336a1cb
Cited by
197
References
246
Citations by year
2026: 23 · 2025: 28 · 2024: 40 · 2023: 44 · 2022: 36 · 2021: 25 · 2020: 1
FWCI
2.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Life Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
Funders
  • AFM-Téléthon (22457)
  • STARSCOG
  • Associazione Italiana per la Ricerca sul Cancro
  • Università degli Studi di Padova
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
mitochondrial network dynamics, mitochondrial fission, mitochondrial fusion, mitophagy, mitochondrial proteolysis, skeletal muscle mass, muscle atrophy, sarcopenia, mitochondrial quality control, physical activity, mitochondrial dysfunction, age-related muscle loss
MeSH terms
Aging, Humans, Mitochondria, Muscular Diseases, Muscle, Skeletal, Proteolysis, Mitochondrial Dynamics, Mitophagy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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