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

In the paper

“MFF overexpression results in increased mitochondrial fission [90, 93].”

What the sources say

• Supported

  The Results section, “Exogenous expression of Mff induces extensive mitochondrial fission,” reports that more than 80% of Mff-transfected HeLa cells had extensively fragmented mitochondria and concludes that Mff promotes mitochondrial fission. The paper also explicitly describes extensive mitochondrial fragmentation following Mff overexpression in the Results section on cytochrome c release. (LLM, conf=0.94)

  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
• Disputed

  The Results directly test Mff overexpression in HeLa cells and report fragmented mitochondria in 6.0 ± 3.8% of transfected cells versus 7.7 ± 1.7% of untransfected cells. The authors conclude that Mff overexpression does not induce fission; the siRNA findings concern Mff depletion, not overexpression. (LLM, conf=0.95)

  Checked by a reasoning model — may be wrong.

  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 sourceExperimental — accuracy not yet measured

In the paper

“Moreover, at least half of the atrogenes require FoxOs for their up- or downregulation [16].”

What the sources say

• Partly supported

  The Results section, “Half of the atrophy-related genes are under FoxO regulation” (page unavailable), reports that 29 of 63 atrophy-related genes require FoxO for normal induction during fasting. That supports a substantial FoxO-dependent share, but 29 of 63 is less than half, and the reported count concerns induction rather than both up- and downregulation. (LLM, conf=0.88)

  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 sourceExperimental — accuracy not yet measured

In the paper

“GTP hydrolysis of MFN1 causes a conformational change that allows the OMMs of opposing mitochondria to contact and fuse [61, 62].”

What the sources say

• Not checked yetcites [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
• Partly supported

  The discussion passage labeled Abstract proposes that, during GTP hydrolysis, MFN1’s HD2 may fold back and bring opposing outer mitochondrial membranes close together. Extended Data Figure 9 presents this as a model and says subsequent membrane merger may depend on local curvature. The claim overstates a proposed mechanism as an established causal sequence through fusion. (LLM, conf=0.86)

  cites [62] Cao Y-L, Meng S, Chen Y et al (2017) MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion. Nature 542:372–376. https://doi.org/10.1038/nature21077 sourceExperimental — accuracy not yet measured

In the paper

“Genetic loss of MFN1 induces a higher degree of mitochondrial fragmentation than MFN2 deletion [60].”

What the sources say

• Supported

  The Results section, under “Both Mfn1- and Mfn2-deficient cells have aberrant mitochondrial morphology,” explicitly states that loss of Mfn1 leads to a greater degree of fragmentation than loss of Mfn2. This directly supports the comparison in the citing sentence. (LLM, conf=0.95)

  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

In the paper

“However, under stress conditions, fusion can rely only on OPA1L, while OPA1S forms are dispensable [76].”

What the sources say

• Supported

  In Results and discussion, under “Long OPA1 forms are sufficient to mediate mitochondrial fusion” (page unavailable), the paper reports that double-knockout cells contain L-OPA1 but no S-OPA1, retain mitochondrial fusion, and undergo stress-induced mitochondrial hyperfusion. This supports the claim that S-OPA1 is dispensable for fusion under the stress condition tested. (LLM, conf=0.91)

  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

In the paper

“Alterations in mitochondrial distribution, morphology, and function are present in atrophic muscles in aging [148–150], muscle disuse [151, 152], burn injury [153], intensive care unit-acquired weakness [154], insulin resistance [155] chronic obstructive pulmonary disease (COPD) [156], cancer cachexia [157–159], and different neuromuscular disorders [160].”

What the sources say

• Partly supported

  Only the aging portion of the citing sentence is attributed to this paper. The Introduction links age-related muscle atrophy to impaired mitochondrial function, and the Results report less mitochondrial volume in both subsarcolemmal and intermyofibrillar regions of old animals’ muscle. The paper does not clearly establish an age-related change in mitochondrial morphology, so it supports only part of the attributed claim. (LLM, conf=0.85)

  cites [148] Ljubicic V, Joseph A-M, Adhihetty PJ et al (2009) Molecular basis for an attenuated mitochondrial adaptive plasticity in aged skeletal muscle. Aging (Albany NY) 1:818–830. https://doi.org/10.18632/aging.100083 sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports altered mitochondrial morphology in atrophied skeletal muscle of aged mice, and the Introduction describes mitochondrial dysfunction in aging muscle. The cited paper does not establish an age-related change in mitochondrial spatial distribution; its reported distributions concern mitochondrial shape measurements. The other conditions in the citing sentence have separate citations and are not attributed to this paper. (LLM, conf=0.84)

  cites [149] Leduc-Gaudet J-P, Picard M, St-Jean Pelletier F et al (2015) Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice. Oncotarget 6:17923–17937. https://doi.org/10.18632/oncotarget.4235 sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction links aging-related muscle loss to mitochondrial dysfunction, and the Discussion describes changes in mitochondrial morphology with aging (page numbers unavailable in our copy). The paper does not establish altered mitochondrial distribution in atrophic muscle. The other conditions in the citing sentence have separate citations and are not attributed to this source. (LLM, conf=0.84)

  cites [150] Faitg J, Leduc-Gaudet J-P, Reynaud O et al (2019) Effects of aging and caloric restriction on fiber type composition, mitochondrial morphology and dynamics in rat oxidative and glycolytic muscles. Front Physiol 10:420. https://doi.org/10.3389/fphys.2019.00420 sourceExperimental — accuracy not yet measured
• Not checked yetcites [151] Iqbal S, Ostojic O, Singh K et al (2013) Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse. Muscle Nerve 48:963–970. https://doi.org/10.1002/mus.23838 source
• Partly supported

  The Introduction and Discussion (page numbers unavailable) link mitochondrial alterations to aging, insulin resistance, disuse-related conditions, burn injury, and cancer; the paper also documents disrupted mitochondrial distribution in denervated and fasted muscle. Our copy does not address intensive care unit-acquired weakness or COPD, and does not establish all three types of alteration—distribution, morphology, and function—for every condition listed. (LLM, conf=0.85)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  Citation [153] is attached to burn injury, not the other conditions listed. The Introduction and “Burn Trauma Induces Mitochondrial Stress in Skeletal Muscle” report muscle wasting and altered mitochondrial function after severe burns, but do not establish altered mitochondrial distribution or morphology in burned muscle. The fragmentation discussed under “Increased Mitochondrial Protein Turnover” concerns mouse embryonic fibroblasts, not burn patients; page numbers were unavailable in our copy. (LLM, conf=0.86)

  cites [153] Ogunbileje JO, Herndon DN, Murton AJ, Porter C (2018) The role of mitochondrial stress in muscle wasting following severe burn trauma. J Burn Care Res 39:100–108. https://doi.org/10.1097/BCR.0000000000000553 sourceExperimental — accuracy not yet measured

In the paper

“OMA1 deficiency causes the lack of processing of OPA1L, which results in the shift of mitochondrial dynamics towards fusion.”

What the sources say

• Supported

  The Discussion states that Oma1-deficient cells lack processing of L-OPA1 and that this shifts mitochondrial dynamics toward fusion. This directly supports the claim. (LLM, conf=0.95)

  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

In the paper

“When OPA1 was deleted during fetal development, animals died a few days after birth.”

What the sources say

• Partly supported

  The Results section, “Muscle-Specific Opa1 Deletion in Newborns Blocks Animal Growth and Is Lethal” (page unavailable), reports that muscle-specific Opa1 knockout mice died within nine days of birth. The Methods describe a constitutive muscle-specific knockout, but our copy does not establish that deletion occurred during fetal development; the claim also omits the muscle-specific qualifier. (LLM, conf=0.83)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  The section ‘Skeletal muscle-specific Opa1 ablation causes reduced body growth and premature death’ reports that Opa1 knockout mice had a dramatically reduced lifespan. It does not report death a few days after birth; the same section describes knockout mice alive at 9 weeks of age. Our copy also does not specify that deletion occurred during fetal development. (LLM, conf=0.88)

  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 sourceExperimental — accuracy not yet measured
• ?Could not verify

  The section on OPA1 deficiency and mitochondrial respiratory capacity says OPA1 was reduced in mice by administering tamoxifen at four weeks of age, not during fetal development. Our copy does not report whether fetal OPA1 deletion caused death after birth; searches for embryonic deletion, neonatal lethality, and birth found no such passage. (LLM, conf=0.74)

  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 sourceExperimental — accuracy not yet measured

In the paper

“There is strong evidence in skeletal muscle that supports a causal link between the dysregulation of mitochondrial fission and alterations in muscle maintenance [152, 196, 197, 210, 211].”

What the sources say

• Supported

  The Abstract reports that inducing mitochondrial fission causes muscle wasting in adult animals, while inhibiting fission reduces muscle loss during fasting and after FoxO3 overexpression. The Discussion likewise reports that activating fission pathways in adult muscle fibres induces atrophy. These intervention findings support the claimed causal link between dysregulated fission and altered muscle maintenance. (LLM, conf=0.93)

  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
• Supported

  The Abstract reports that muscle-specific loss of the fission protein DRP1 induces muscle wasting and weakness, with inducible deletion causing atrophy and degeneration. The Introduction also describes skeletal-muscle mouse models lacking Drp1 that develop myopathy, supporting a causal link between disrupted fission and impaired muscle maintenance. (LLM, conf=0.94)

  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
• Supported

  The Introduction reports that both inhibition and overexpression of fission proteins in skeletal muscle cause weakness, wasting, or atrophy. The Discussion also reports that reducing Drp1 alongside Opa1 alleviates detrimental effects of unbalanced mitochondrial dynamics. These intervention findings support a causal link between dysregulated fission and muscle maintenance. (LLM, conf=0.93)

  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
• Supported

  The Discussion reports that skeletal-muscle-specific overexpression of the fission protein Drp1 reorganized mitochondria and impaired postnatal muscle development. It concludes that an altered balance between fission and fusion impairs muscle growth and links Drp1-dependent signaling to muscle homeostasis. (LLM, conf=0.90)

  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
• Partly supported

  The Results section ('Dnm1L is critical for exercise performance and training adaptations in muscle'; page unavailable) reports that mice with reduced muscle Drp1 had a smaller training-induced increase in muscle-fiber cross-sectional area. This supports a causal role for Drp1 in a muscle adaptation, but the paper does not establish that altered mitochondrial fission itself caused a general change in muscle maintenance; the Discussion notes that Drp1 has other functions. (LLM, conf=0.85)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Interestingly, a mild inhibition of OPA1, which does not alter mitochondrial complex and supercomplex formation as well as mitochondrial DNA content and citrate synthase activity, in muscle during neonatal growth results in several beneficial metabolic changes in terms of resistance to obesity when the animals were challenged with a high-fat diet [193].”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  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 sourceExperimental — accuracy not yet measured

In the paper

“Mutations in DRP1 lead to a severe neurological syndrome with microencephaly, hypotonia, alterations in brain development, and metabolism that cause neonatal lethality due to multi-system damage [201–203].”

What the sources say

• Not checked yetcites [201] Waterham HR, Koster J, van Roermund CWT et al (2007) A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med 356:1736–1741. https://doi.org/10.1056/NEJMoa064436 source
• Not checked yetcites [202] Yoon G, Malam Z, Paton T et al (2016) Lethal disorder of mitochondrial fission caused by mutations in DNM1L. J Pediatr 171:313-316.e1–2. https://doi.org/10.1016/j.jpeds.2015.12.060 source
• Partly supported

  The Introduction (page unavailable) reports neonatal lethality in previously described DNM1L cases, and the Abstract describes cerebral dysgenesis and metabolic abnormalities in one lethal case. The paper does not establish microencephaly or hypotonia as features of the syndrome, or neonatal lethality as the outcome of DNM1L mutations generally: its own patient survived to age seven with normal metabolic screening tests. (LLM, conf=0.88)

  cites [203] Vanstone JR, Smith AM, McBride S et al (2016) DNM1L-related mitochondrial fission defect presenting as refractory epilepsy. Eur J Hum Genet 24:1084–1088. https://doi.org/10.1038/ejhg.2015.243 sourceExperimental — accuracy not yet measured

In the paper

“Interestingly, the stress-response myokine FGF21 is dramatically increased in muscle and serum of all these three models, even if with a different degree.”

What the sources say

• Partly supported

  The Results section on Opa1 deletion reports that FGF21 was massively upregulated in skeletal muscle and rose in circulating blood. Our copy does not report corresponding muscle and serum increases in DRP1 or OPA1/DRP1 double-knockout models, so it does not support the claim about all three models or their differing degrees of increase (page unavailable). (LLM, conf=0.90)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results sections report increased muscle FGF21 expression and blood FGF21 in DRP1-knockout mice, including a 20-fold blood increase after acute deletion. The Discussion describes FGF21 induction after OPA1 ablation and says serum levels are higher in OPA1-knockout than DRP1-knockout mice. Our copy does not report FGF21 levels in an OPA1/DRP1 double-knockout (DKO) model, so it does not support the claim for all three models. (LLM, conf=0.87)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  Results §3.4 reports that FGF21 in DKO muscle and blood peaked at 70 days but returned to control levels by 365 days. The Discussion also describes elevated circulating FGF21 in Opa1-deleted mice. The paper does not establish increased FGF21 in both muscle and serum of a DRP1-only model, so it does not support the claim for all three models. (LLM, conf=0.87)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Several reports have shown that rebalancing of mitochondrial dynamics rescues the phenotype of certain diseases associated with alterations of mitochondrial fusion or fission [119, 194, 195, 214]”

What the sources say

• Partly supported

  The Discussion (page unavailable) reports that increasing fission through PUM2 loss rescues abnormal mitochondrial networks in old worms and mice. That supports rescue of an age-associated phenotype, but the paper does not establish rescue of phenotypes in diseases associated with altered mitochondrial fusion or fission. (LLM, conf=0.84)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page not provided) reports that OPA1 overexpression protects against several forms of tissue damage and counteracts myopathy caused by a genetic mitochondrial defect. The paper identifies OPA1 as a fusion protein, but attributes protection chiefly to cristae maintenance; it does not establish that rebalancing fusion and fission rescues diseases caused by alterations in those processes. (LLM, conf=0.86)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results report that Opa1 overexpression improved disease phenotypes in two mouse models, supporting the rescue component of the claim. But the Introduction identifies these as models of respiratory-chain complex I and IV deficiency, not diseases caused by altered mitochondrial fusion or fission. The Discussion attributes the improvement to cristae and respiratory-chain stabilization; it does not establish that rebalancing fusion and fission rescued the phenotypes. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports that promoting mitochondrial fission rescues several degenerative phenotypes in PINK1 and Parkin mutant flies. This supports rescue in disease-associated fly models, but the paper does not establish that rebalancing mitochondrial dynamics rescues the phenotypes of diseases themselves more generally. (LLM, conf=0.82)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The Methods section describes a constitutive, muscle-specific Drp1 knockout, and the Results report reduced DRP1 in newborn muscle, reduced growth during the first 17 postnatal days, and death within 30 days. The Results also report muscle loss and, after prolonged deletion, myofiber degeneration following inducible DRP1 ablation in adults. The paper does not specify the embryonic day of deletion, but its constitutive model had lost muscle DRP1 by birth. (LLM, conf=0.90)

  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

In the paper

“Therefore, by controlling FoxOs and mTOR, AKT is a regulatory node between catabolic and anabolic processes.”

In the paper

“The mitochondrial muscle reticulum forms a conductive pathway that can rapidly transfer energy from the oxygen source, the capillary, to the contractile apparatus [24].”

What the sources say

• Not checked yetcites [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

In the paper

“The dynamic coordination of processes controlling the quality of the mitochondrial network is crucial to maintain the function of mitochondria in skeletal muscle.”

In the paper

“In addition to SS and IMF connection, mitochondria also communicate among themselves through intermitochondrial junctions (IMJs) and nanotunnels.”

In the paper

“Muscle-specific inhibition of FoxOs protects from cancer cachexia-, fasting-, hindlimb suspension- or denervation-induced atrophy [16–18].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“These tubular structures can transport ions, metabolites, and proteins, between spatially restricted mitochondria like the myofibril-embedded IMF [21].”

What the sources say

• Not checked yetcites [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

In the paper

“Muscle atrophy requires the activation of gene transcription programs that regulate the expression of a subset of genes that are named atrophy-related genes or atrogenes [10–14].”

What the sources say

• Not checked yetcites [10] Bodine SC, Latres E, Baumhueter S et al (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294:1704–1708. https://doi.org/10.1126/science.1065874 source
• Not checked yetcites [11] Lecker SH, Jagoe RT, Gilbert A et al (2004) Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J 18:39–51. https://doi.org/10.1096/fj.03-0610com source
• Not checked yetcites [12] Gomes MD, Lecker SH, Jagoe RT et al (2001) Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci USA 98:14440–14445. https://doi.org/10.1073/pnas.251541198 source
• Not checked yetcites [13] Sacheck JM, Hyatt J-PK, Raffaello A et al (2007) Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases. FASEB J 21:140–155. https://doi.org/10.1096/fj.06-6604com source
• Not checked yetcites [14] Taillandier D, Polge C (2019) Skeletal muscle atrogenes: from rodent models to human pathologies. Biochimie 166:251–269. https://doi.org/10.1016/j.biochi.2019.07.014 source

In the paper

“However, muscle atrophy involves not only the breakdown of the myofibrils but also the loss of organelles like mitochondria.”

In the paper

“These structures allow the coordination of cristae orientation and electrical coupling between adjacent mitochondria within the mitochondrial network [27].”

What the sources say

• Not checked yetcites [27] Picard M, McManus MJ, Csordás G et al (2015) Trans-mitochondrial coordination of cristae at regulated membrane junctions. Nat Commun 6:6259. https://doi.org/10.1038/ncomms7259 source

In the paper

“FoxO family of transcription factors (FoxO1, FoxO3, and FoxO4) are critical mediators of the catabolic response during atrophy [9, 15, 16].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [15] Mammucari C, Milan G, Romanello V et al (2007) FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6:458–471. https://doi.org/10.1016/j.cmet.2007.11.001 source
• Not checked yetcites [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

In the paper

“Changes of mitochondrial proteolytic system, dynamics (fusion/fission), and mitophagy induce pathways that affect muscle mass and performance.”

In the paper

“Muscles that produce a long-lasting contraction, like postural muscles, are mainly composed of slow b-oxidative fibers, which have high mitochondrial content, increased reliance on OXPHOS, and are resistant to fatigue.”

In the paper

“Adult myofibers have a specific subcellular distribution of distinctive mitochondria populations that have been classified accordingly to their localization as subsarcolemmal and intermyofibrillar.”

In the paper

“Accordingly, inhibition of SMAD 2 and SMAD 3 is sufficient to induce muscle growth [4, 5].”

What the sources say

• Not checked yetcites [4] Sartori R, Milan G, Patron M et al (2009) Smad2 and 3 transcription factors control muscle mass in adulthood. Am J Physiol Cell Physiol 296:C1248-1257. https://doi.org/10.1152/ajpcell.00104.2009 source
• Not checked yetcites [5] Trendelenburg AU, Meyer A, Rohner D et al (2009) Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am J Physiol Cell Physiol 296:C1258-1270. https://doi.org/10.1152/ajpcell.00105.2009 source

In the paper

“Mechanical overload or anabolic hormonal stimulation shifts the balance toward protein synthesis with consequent increases in fiber size, called hypertrophy.”

In the paper

“More than 10% of the atrophy-related genes are directly involved in energy production.”

In the paper

“Genes encoding for glycolysis and oxidative phosphorylation enzymes are coordinately suppressed in atrophying muscles during denervation, disuse, diabetes, cancer, fasting, and chronic kidney disease [10, 11, 13, 20].”

What the sources say

• Not checked yetcites [10] Bodine SC, Latres E, Baumhueter S et al (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294:1704–1708. https://doi.org/10.1126/science.1065874 source
• Not checked yetcites [11] Lecker SH, Jagoe RT, Gilbert A et al (2004) Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J 18:39–51. https://doi.org/10.1096/fj.03-0610com source
• Not checked yetcites [13] Sacheck JM, Hyatt J-PK, Raffaello A et al (2007) Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases. FASEB J 21:140–155. https://doi.org/10.1096/fj.06-6604com source
• Not checked yetcites [20] Ebert SM, Dyle MC, Kunkel SD et al (2012) Stress-induced skeletal muscle Gadd45a expression reprograms myonuclei and causes muscle atrophy. J Biol Chem 287:27290–27301. https://doi.org/10.1074/jbc.M112.374777 source

In the paper

“Recent data show that retrograde signaling from the mitochondrial network to the nucleus adapts muscle function to the physiological or pathological demands.”

In the paper

“Importantly, the overexpression of ATF4 and GADD45 is sufficient to induce muscle loss [19, 20].”

What the sources say

• Not checked yetcites [19] Ebert SM, Monteys AM, Fox DK et al (2010) The transcription factor ATF4 promotes skeletal myofiber atrophy during fasting. Mol Endocrinol 24:790–799. https://doi.org/10.1210/me.2009-0345 source
• Not checked yetcites [20] Ebert SM, Dyle MC, Kunkel SD et al (2012) Stress-induced skeletal muscle Gadd45a expression reprograms myonuclei and causes muscle atrophy. J Biol Chem 287:27290–27301. https://doi.org/10.1074/jbc.M112.374777 source

In the paper

“This finding suggests that alterations in the mitochondrial network contribute to muscle atrophy.”

In the paper

“Energy requirements during intense contraction in skeletal muscles increase to 100-fold the consumption of ATP [3].”

What the sources say

• Not checked yetcites [3] Gaitanos GC, Williams C, Boobis LH, Brooks S (1993) Human muscle metabolism during intermittent maximal exercise. J Appl Physiol 75:712–719. https://doi.org/10.1152/jappl.1993.75.2.712 source

In the paper

“Myostatin-dependent recruitment of SMAD 2/3 is a negative regulator of muscle mass [3].”

What the sources say

• Not checked yetcites [3] Gaitanos GC, Williams C, Boobis LH, Brooks S (1993) Human muscle metabolism during intermittent maximal exercise. J Appl Physiol 75:712–719. https://doi.org/10.1152/jappl.1993.75.2.712 source

In the paper

“The ultimate purpose of UPRmt is to maintain proteostasis by promoting the expression of chaperones and m-AAA proteases ClpP and YME1L1, inside mitochondria.”

In the paper

“In mouse cardiac muscle, the UPS ubiquitinates several OMM, IMS, and matrix mitochondrial proteins [39, 40].”

What the sources say

• Not checked yetcites [39] Jeon HB, Choi ES, Yoon JH et al (2007) A proteomics approach to identify the ubiquitinated proteins in mouse heart. Biochem Biophys Res Commun 357:731–736. https://doi.org/10.1016/j.bbrc.2007.04.015 source
• Not checked yetcites [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

In the paper

“Therefore, the mitochondrial network morphology, arrangement, and connectivity adapt to each fiber type's specific functional needs (e.g., OXPHOS capacity and contractility) [31, 32].”

What the sources say

• Not checked yetcites [31] Mishra P, Varuzhanyan G, Pham AH, Chan DC (2015) Mitochondrial dynamics is a distinguishing feature of skeletal muscle fiber types and regulates organellar compartmentalization. Cell Metab 22:1033–1044. https://doi.org/10.1016/j.cmet.2015.09.027 source
• Not checked yetcites [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

In the paper

“Protein degradation in the IMS is controlled by the membrane-bound i-AAA YME1L1, the soluble HtrA2/OMI, the metallopeptidases OMA1 and the rhomboid protease PARL.”

In the paper

“Mitochondrial shape and function are strictly connected.”

In the paper

“The mitochondrial conformation within myofibers has a fiber-type-dependent specific pattern.”

In the paper

“The rapid morphological adaptations, by balanced fusion and fission, are crucial to counteract defective components' accumulation within the mitochondrial network.”

In the paper

“PARL modulates mitophagy by degrading the mitophagy protein PINK1 [38].”

What the sources say

• Not checked yetcites [38] Jin SM, Lazarou M, Wang C et al (2010) Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol 191:933–942. https://doi.org/10.1083/jcb.201008084 source

In the paper

“The OMM fusion is controlled by the OMM membrane-bound GTPases mitofusin 1 (MFN1) and mitofusin 2 (MFN2).”

In the paper

“The mitochondrial connectivity within the network through IMJs is higher in oxidative than in glycolytic fibers, reflecting the cell's functional demands.”

In the paper

“An essential mitochondrial quality control system is the dynamic remodeling of mitochondrial membranes, through repeated rounds of fusion and fission events.”

In the paper

“Interestingly, proteasome inhibition leads to accumulating the IMM proteins UCP2, COXI, III, IV, and OSCP [51].”

What the sources say

• Not checked yetcites [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

In the paper

“Oxidative fibers have a grid-like mitochondrial network conformation, with parallel and perpendicularly oriented elongated mitochondria.”

In the paper

“The first line of defense against mild mitochondrial damage involves the degradation of misfolded or oxidized proteins by activating specific mitochondrial proteases in each mitochondrial compartment.”

In the paper

“A recent proteomic study in Drosophila fibroblasts identified that most of the mitochondrial protein turnover (70% circa) occurs through the combination of non-autophagic degradative processes like mitochondrial proteases, the ubiquitin–proteasome system, and mitochondrial-derived vesicles; while the contribution of mitophagy to protein turnover is of the remaining one third [36].”

What the sources say

• Not checked yetcites [36] Vincow ES, Thomas RE, Merrihew GE et al (2019) Autophagy accounts for approximately one-third of mitochondrial protein turnover and is protein selective. Autophagy 15:1592–1605. https://doi.org/10.1080/15548627.2019.1586258 source

In the paper

“Similarly, defects in the fission machinery can lead to a hyper fused mitochondrial network that hinders an efficient mitophagy process.”

In the paper

“These are the AAA ATPase p97, also referred to as valosin-containing protein (VCP), and the cofactor Npl4, both involved in the process of pulling out ubiquitinated proteins from the OMM and retrotranslocation to the cytosol [48].”

What the sources say

• Not checked yetcites [48] Heo J-M, Livnat-Levanon N, Taylor EB et al (2010) A stress-responsive system for mitochondrial protein degradation. Mol Cell 40:465–480. https://doi.org/10.1016/j.molcel.2010.10.021 source

In the paper

“For example, m-AAA, YME1L1, HtrA2, OMA1, and PARL cleave the profusion protein OPA1 affecting mitochondrial morphology and function [37].”

What the sources say

• Not checked yetcites [37] Ahola S, Langer T, MacVicar T (2019) Mitochondrial proteolysis and metabolic control. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a033936 source

In the paper

“The continuous alternation of these two processes regulates mitochondrial number, morphology, and distribution, ensuring the adaptation of the mitochondrial network to the cellular bioenergetic requirements.”

In the paper

“p97 provides the driving force to extract Mfn1, Mfn2, and the anti-apoptotic protein MCL1 from the OMM and chaperone them to the proteasome [49, 50].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Thus, repairing and restoring mitochondrial proteostasis complex is critical for the adaptation to environmental changes that risk mitochondrial proteome integrity and, consequently, limit the mitochondrial damage.”

In the paper

“In the absence of DRP1 or OMM constriction, the IMM division still occurs, indicating the presence of an inner membrane fission machinery independent of DRP1 [100, 101].”

What the sources say

• Not checked yetcites [100] Labrousse AM, Zappaterra MD, Rube DA, van der Bliek AM (1999) C. elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane. Mol Cell 4:815–826. https://doi.org/10.1016/s1097-2765(00)80391-3 source
• Not checked yetcites [101] Fujioka H, Tandler B, Hoppel CL (2012) Mitochondrial division in rat cardiomyocytes: an electron microscope study. Anat Rec (Hoboken) 295:1455–1461. https://doi.org/10.1002/ar.22523 source

In the paper

“OPA1 activity is regulated by proteolytic processing.”

In the paper

“DRP1-dependent mitochondrial fission through MiD49 and/or MiD51, but not MFF, is required for cristae remodeling to facilitate cytochrome c release into the cytoplasm during apoptosis [97].”

What the sources say

• Not checked yetcites [97] Otera H, Miyata N, Kuge O, Mihara K (2016) Drp1-dependent mitochondrial fission via MiD49/51 is essential for apoptotic cristae remodeling. J Cell Biol 212:531–544. https://doi.org/10.1083/jcb.201508099 source

In the paper

“The E3 ligases HUWE1 also promotes MFN2 ubiquitination and proteasomal degradation [70].”

What the sources say

• Not checked yetcites [70] Leboucher GP, Tsai YC, Yang M et al (2012) Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptosis. Mol Cell 47:547–557. https://doi.org/10.1016/j.molcel.2012.05.041 source

In the paper

“The mitoproteases OMA1 and YME1L cleave OPA1 under different physiological conditions.”

In the paper

“An initial constriction before DRP1action is necessary because the DRP1 spiral is narrower than the mitochondrial diameter.”

In the paper

“Fission occurs at mitochondria–ER contact sites marked with mtDNA [80].”

What the sources say

• Not checked yetcites [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

In the paper

“YME1L1 cuts the site S2 in exon 5b of a subset of OPA1L belonging to the splicing variants 4, 6, 7, and 8 [76] under high OXPHOS conditions [77].”

What the sources say

• Not checked yetcites [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 yetcites [77] Mishra P, Carelli V, Manfredi G, Chan DC (2014) Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation. Cell Metab 19:630–641. https://doi.org/10.1016/j.cmet.2014.03.011 source

In the paper

“Instead, it has been reported that other components of the mammalian fission bind to DRP1 and arrange the assembly of DRP1 oligomers at constriction sites: mitochondrial fission factor (MFF), mitochondrial elongation factor 2/mitochondrial dynamics protein 49 (MIEF2/MiD49), and MIEF1/MiD51 [90–93].”

What the sources say

• Not checked yetcites [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 yetcites [91] Palmer CS, Osellame LD, Laine D et al (2011) MiD49 and MiD51, new components of the mitochondrial fission machinery. EMBO Rep 12:565–573. https://doi.org/10.1038/embor.2011.54 source
• Not checked yetcites [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 yetcites [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

In the paper

“This process might be facilitated by the action of the ER protein inverted formin 2 (INF2), which induces actin polymerization at the ER–mitochondria contact sites, enabling force generation to drive initial mitochondrial constriction [82].”

What the sources say

• Not checked yetcites [82] Korobova F, Ramabhadran V, Higgs HN (2013) An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2. Science 339:464–467. https://doi.org/10.1126/science.1228360 source

In the paper

“Upon OMM fusion, the optic atrophy protein 1 (OPA1), a dynamin-like GTPase located in the IMM, is required for IMM fusion [72].”

What the sources say

• Not checked yetcites [72] Ban T, Ishihara T, Kohno H et al (2017) Molecular basis of selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin. Nat Cell Biol 19:856–863. https://doi.org/10.1038/ncb3560 source

In the paper

“Here, ER tubules wrap around mitochondria and promote an initial reduction of the mitochondrial diameter in a process termed ER-associated mitochondrial division (ERMD) [81].”

What the sources say

• Not checked yetcites [81] Friedman JR, Lackner LL, West M et al (2011) ER tubules mark sites of mitochondrial division. Science 334:358–362. https://doi.org/10.1126/science.1207385 source

In the paper

“The association of mitochondria with the ER is required to identify the scission site in the mitochondrial network.”

In the paper

“For instance, when PINK1 phosphorylates MFN2, it becomes a receptor for the ubiquitin ligase Parkin to activate mitophagy [69].”

What the sources say

• Not checked yetcites [69] Chen Y, Dorn GW (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340:471–475. https://doi.org/10.1126/science.1231031 source

In the paper

“Fusion is also enhanced by the interaction between OPA1L and the IMM lipid, cardiolipin [72].”

What the sources say

• Not checked yetcites [72] Ban T, Ishihara T, Kohno H et al (2017) Molecular basis of selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin. Nat Cell Biol 19:856–863. https://doi.org/10.1038/ncb3560 source

In the paper

“OPA1L is anchored to the IMM by a transmembrane domain at the N-terminus and can be further cleaved in exon 5 (site S1) by OMA1, a process which depends on the mitochondrial membrane potential [75].”

What the sources say

• Not checked yetcites [75] Head B, Griparic L, Amiri M et al (2009) Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J Cell Biol 187:959–966. https://doi.org/10.1083/jcb.200906083 source

In the paper

“Mitochondrial fusion rates correlate with the OXPHOS capacity, higher in oxidative fibers than in glycolytic fibers [60].”

What the sources say

• Not checked yetcites [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

In the paper

“The first case of homozygous missense mutation has been recently reported in two sisters. They died at 2 and 10 months of age, showing myopathy, encephalopathy, and cardiomyopathy [184].”

What the sources say

• Not checked yetcites [184] Spiegel R, Saada A, Flannery PJ et al (2016) Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation. J Med Genet 53:127–131. https://doi.org/10.1136/jmedgenet-2015-103361 source

In the paper

“PARL levels are reduced in skeletal muscle during aging and type 2 diabetes mellitus [168].”

What the sources say

• Not checked yetcites [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

In the paper

“Muscle biopsies from these patients display alterations in cristae morphology and paracrystalline inclusions and fiber-type grouping, indicating denervation [165].”

What the sources say

• Not checked yetcites [165] Hartmann B, Wai T, Hu H et al (2016) Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation. Elife. https://doi.org/10.7554/eLife.16078 source

In the paper

“In line with the reports suggesting a link between mitochondrial calcium overload and mitochondrial fragmentation [104, 105], MCU inhibition leads to mitochondrial elongation [103].”

What the sources say

• Not checked yetcites [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

In the paper

“In mice, the homozygous deletion of LonP1 causes early embryonic death [161].”

What the sources say

• Not checked yetcites [161] Quirós PM, Español Y, Acín-Pérez R et al (2014) ATP-dependent Lon protease controls tumor bioenergetics by reprogramming mitochondrial activity. Cell Rep 8:542–556. https://doi.org/10.1016/j.celrep.2014.06.018 source

In the paper

“This recovery is because the loss of YME1L in skeletal muscle and the consequent mitochondrial dysfunction triggers systemic glucose intolerance and lowers insulin levels preventing cardiac glucose overload and cardiomyopathy [166].”

What the sources say

• Not checked yetcites [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

In the paper

“Thus, Yme1L1 is essential for normal cardiac function.”

In the paper

“The matrix mitochondrial protease LonP1 is necessary for the maintenance of mitochondrial matrix proteostasis.”

What the sources say

• Not checked yetcites [161] Quirós PM, Español Y, Acín-Pérez R et al (2014) ATP-dependent Lon protease controls tumor bioenergetics by reprogramming mitochondrial activity. Cell Rep 8:542–556. https://doi.org/10.1016/j.celrep.2014.06.018 source
• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“Similarly, the inhibition of p97/VCP in zebrafish leads to mitochondrial morphology and cristae alterations in skeletal muscle and the heart [175].”

What the sources say

• Not checked yetcites [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

In the paper

“Its gene disruption causes early embryonic lethality in mice, highlighting the importance of maintaining proteostasis during embryogenesis [170].”

What the sources say

• Not checked yetcites [170] Müller JMM, Deinhardt K, Rosewell I et al (2007) Targeted deletion of p97 (VCP/CDC48) in mouse results in early embryonic lethality. Biochem Biophys Res Commun 354:459–465. https://doi.org/10.1016/j.bbrc.2006.12.206 source

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“The accumulation of damaged proteins due to a homozygous missense mutation that impairs the IMS protease maturation, YME1L1, causes infantile onset mitochondriopathy with severe intellectual disability, muscular impairments, and optic nerve atrophy.”

What the sources say

• Not checked yetcites [165] Hartmann B, Wai T, Hu H et al (2016) Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation. Elife. https://doi.org/10.7554/eLife.16078 source

In the paper

“OPA1 heterozygous missense recessive mutations cause DOA characterized by an aspecific myopathy with mitochondrial features [182, 183].”

What the sources say

• Not checked yetcites [182] Schaaf CP, Blazo M, Lewis RA et al (2011) Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations. Mol Genet Metab 103:383–387. https://doi.org/10.1016/j.ymgme.2011.04.018 source
• Not checked yetcites [183] Amati-Bonneau P, Valentino ML, Reynier P et al (2008) OPA1 mutations induce mitochondrial DNA instability and optic atrophy “plus” phenotypes. Brain 131:338–351. https://doi.org/10.1093/brain/awm298 source

In the paper

“The relevance of mitochondrial retrotranslocation mechanism in quality control has been demonstrated by the direct link between p97/VCP mutation and human neuromuscular diseases, like Inclusion Body Myopathy, Frontotemporal dementia and Amyotrophic Lateral Sclerosis [171, 172].”

What the sources say

• Not checked yetcites [171] Watts GDJ, Wymer J, Kovach MJ et al (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36:377–381. https://doi.org/10.1038/ng1332 source
• Not checked yetcites [172] Johnson JO, Mandrioli J, Benatar M et al (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68:857–864. https://doi.org/10.1016/j.neuron.2010.11.036 source

In the paper

“Therefore, post-mitotic tissues depend on the activation of coordinated pathways to preserve or restore mitochondrial function.”

In the paper

“Interestingly, during muscle atrophy, induction of p97/VCP occurs when protein breakdown is maximal in myofibers [177].”

What the sources say

• Not checked yetcites [177] Piccirillo R, Goldberg AL (2012) The p97/VCP ATPase is critical in muscle atrophy and the accelerated degradation of muscle proteins. EMBO J 31:3334–3350. https://doi.org/10.1038/emboj.2012.178 source

In the paper

“In skeletal muscle, p97/VCP is critical in extracting ubiquitinated proteins from myofibrils during fasting- and denervation-induced atrophy.”

What the sources say

• Not checked yetcites [177] Piccirillo R, Goldberg AL (2012) The p97/VCP ATPase is critical in muscle atrophy and the accelerated degradation of muscle proteins. EMBO J 31:3334–3350. https://doi.org/10.1038/emboj.2012.178 source

In the paper

“Accordingly, inhibition of MFN1 GTPase activity leads to mitochondrial fragmentation and dysfunction that contribute to heart failure progression in mice [191].”

What the sources say

• Not checked yetcites [191] Ferreira JCB, Campos JC, Qvit N et al (2019) A selective inhibitor of mitofusin 1-βIIPKC association improves heart failure outcome in rats. Nat Commun 10:329. https://doi.org/10.1038/s41467-018-08276-6 source

In the paper

“Patients with mutations in the DRP1 receptor MFF, suffer from developmental delay and acquired microcephaly, seizures, spasticity, and optic atrophy [204, 205].”

What the sources say

• Not checked yetcites [204] Shamseldin HE, Alshammari M, Al-Sheddi T et al (2012) Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes. J Med Genet 49:234–241. https://doi.org/10.1136/jmedgenet-2012-100836 source
• Not checked yetcites [205] Koch J, Feichtinger RG, Freisinger P et al (2016) Disturbed mitochondrial and peroxisomal dynamics due to loss of MFF causes Leigh-like encephalopathy, optic atrophy and peripheral neuropathy. J Med Genet 53:270–278. https://doi.org/10.1136/jmedgenet-2015-103500 source

In the paper

“Importantly, MFN2 deficiency during aging is contributes to mitophagy flux inhibition and the accumulation of dysfunctional mitochondria driving age-associated metabolic alterations and sarcopenia [186].”

What the sources say

• Not checked yetcites [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

In the paper

“Disrupted mitochondrial fission, obtained with the specific ablation of DRP1 in the heart, induces accumulation of defective mitochondria due to impaired autophagy/mitophagy, that over-time promotes cardiomyocyte death [198–200].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“Accordingly, the reduction of the mitochondrial fusion machinery in muscle has been linked to age-related sarcopenia [185–187], and metabolic diseases like obesity and type 2 diabetes [188, 189] in both rodents and humans.”

What the sources say

• Not checked yetcites [185] Ibebunjo C, Chick JM, Kendall T et al (2013) Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia. Mol Cell Biol 33:194–212. https://doi.org/10.1128/MCB.01036-12 source
• Not checked yetcites [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 yetcites [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 yetcites [188] Bach D, Naon D, Pich S et al (2005) Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6. Diabetes 54:2685–2693. https://doi.org/10.2337/diabetes.54.9.2685 source
• Not checked yetcites [189] Hernández-Alvarez MI, Thabit H, Burns N et al (2010) Subjects with early-onset type 2 diabetes show defective activation of the skeletal muscle PGC-1{alpha}/Mitofusin-2 regulatory pathway in response to physical activity. Diabetes Care 33:645–651. https://doi.org/10.2337/dc09-1305 source

In the paper

“Consistent with the other OPA1 knockout mice, also in this model, the metabolic changes are mediated by the muscle secretion of FGF21, whose level was mildly increased when compared to the ones present in mice in which OPA1 is completely deleted in adulthood.”

What the sources say

• Not checked yetcites [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

In the paper

“Inhibition of the IMM profusion factor, OPA1, in muscle resulted in a similar but more severe phenotype than skeletal muscle MFN1 and MFN2 ablation [187, 192, 193].”

What the sources say

• Not checked yetcites [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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In the paper

“Muscle-specific simultaneous ablation of MFN1 and MFN2 induces profound muscle atrophy.”

What the sources say

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In the paper

“Consistent with this crucial role, conditional ablation of DRP1 in the heart, brain, and skeletal muscle causes lethality [196, 198–200, 208, 209].”

What the sources say

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In the paper

“Therefore, mutations in fusion genes result in brain and muscle dysfunction.”

In the paper

“Muscle loss in aging sarcopenia [185, 187, 215], cancer cachexia, chemotherapy-induced cachexia [157–159], and in a model of myasthenia gravis [216], is characterized by the decline of both fusion and fission machinery.”

What the sources say

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In the paper