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

In the paper

“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].”

What the sources say

• Supported

  The Results identify MITOL-mediated K63-linked polyubiquitination of Mfn2 and report that MITOL does not promote Mfn2 degradation. The Discussion states that this ubiquitination activates Mfn2 and leads to oligomerization for MAM formation; the paper’s Summary also reports MAM dysfunction after MITOL knockdown. (LLM, conf=0.93)

  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

In the paper

“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].”

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
• Supported

  In “Generation of mice deficient in OMA1” (page not provided), the paper reports that Oma1-null mice were born at the expected Mendelian ratio and developed normally, and explicitly concludes that OMA1 is dispensable for embryonic and adult mouse development. Its OPA1-processing results show altered processing in the deficient mice, supporting the claim about OMA1-induced processing. (LLM, conf=0.92)

  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

“p97/VCP is critical in the retrotranslocation and degradation of endoplasmic reticulum-associated proteins (ERAD) [47] and mitochondrial proteins ( MAD) [49, 50].”

What the sources say

• Not checked yetcites [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
• Partly supported

  The Results section (‘Role of p97 in Mfn proteasomal degradation’; page unavailable) reports that inhibiting p97 largely prevented Parkin-mediated degradation of the mitochondrial proteins Mfn1 and Mfn2. It explicitly says how these proteins are extracted from the outer mitochondrial membrane is unknown, so it does not establish p97’s role in their retrotranslocation. The ERAD portion of the citing sentence is attached to a different citation, [47]. (LLM, conf=0.88)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Discussion report that p97 drives retrotranslocation and proteasomal degradation of the outer mitochondrial membrane proteins Mcl1 and Mfn1, supporting the mitochondrial portion of the citation. The claim says “mitochondrial proteins” more broadly, while the Discussion says the extent of p97’s role in mitochondrial proteostasis remains unclear. The ERAD portion is attached to a different citation [47]. (LLM, conf=0.82)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  The Results (mCK-CAR-PARL(−) mice and impaired insulin-signaling sections; page unavailable) report disorganized cristae, elevated oxidative damage, and impaired insulin signaling after muscle PARL knockdown. The Discussion proposes PARL-mediated OPA1 cleavage as an explanation for the cristae changes and for reduced energetic capacity and elevated ROS in PARL-depleted myotubes. It does not establish reduced OPA1 processing as the explanation for impaired insulin signaling in mouse muscle. (LLM, conf=0.86)

  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 sourceExperimental — accuracy not yet measured

In the paper

“In mice, MFF deletion leads to smaller animals that display neuromuscular defects, kyphosis, and premature death at 13 weeks due to dilated cardiomyopathy [207].”

What the sources say

• Supported

  In Results and discussion, “Mff-deficient mice exhibit pleiotropic phenotypes” reports that Mff gene-trap mutants are smaller, have kyphosis and neuromuscular defects, and die at a mean age of 13 weeks from dilated cardiomyopathy. The “Dilated cardiomyopathy leads to heart failure” section confirms the cause of early death. No page numbers are provided in our copy. (LLM, conf=0.95)

  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

In the paper

“MFN2 deletion in young muscle causes extensive mitochondrial fragmentation, mitochondrial dysfunction, ROS production, ER stress, and autophagy inhibition resulting in muscle atrophy [67, 186].”

What the sources say

• Partly supported

  The Results report mitochondrial dysfunction, increased hydrogen peroxide, and ER stress in Mfn2-deficient muscle. The Discussion describes larger mitochondria in skeletal muscle, not extensive fragmentation; our copy does not establish that deletion in young muscle inhibits autophagy or results in muscle atrophy. (LLM, conf=0.90)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results report muscle atrophy in young Mfn2KO mice, reduced oxidative capacity, increased oxidative stress, and impaired mitochondrial autophagy; rescue experiments link the autophagy defect to atrophy. The copy does not show extensive mitochondrial fragmentation or ER stress in young muscle (searched for fragmentation, ER stress, and unfolded protein response). (LLM, conf=0.88)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Moreover, muscle denervation, oxidative stress, and inflammation are mitigated in DKO muscles, rescuing the lethal phenotype of OPA1 knockout mice [197].”

What the sources say

• Supported

  The Discussion states the claim directly. Results §3.4 also reports mitigated denervation, oxidative stress, and inflammation in DKO muscles, with survival matching controls rather than the premature death seen after Opa1 deletion alone. (LLM, conf=0.95)

  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

In the paper

“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].”

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

“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.”

In the paper

“Moreover, mitochondrial function and, thus, energy production are generally reduced during muscle wasting.”

In the paper

“Conversely, in catabolic conditions, protein degradation exceeds protein synthesis leading to muscle weakness and muscle atrophy.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

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
• Not checked yetcites [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

In the paper

“The IGF1–AKT-–mTOR axis increases protein synthesis by stimulating the translational machinery and simultaneously blocks FoxOs transcription factors and protein degradation [9].”

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“The muscle mass in adulthood is defined by the dynamic balance between protein synthesis and protein degradation.”

In the paper

“On the other hand, BMP signaling is a positive regulator of muscle mass and is dominant over the myostatin pathway [6, 7].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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].”

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
• 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
• Not checked yetcites [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

In the paper

“Instead, maintaining a healthy skeletal muscle mass is associated with a lower risk of mortality [1, 2]”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

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

In the paper

“Nanotunnels are conserved OMM and IMM double-membrane projections, connecting two non-adjacent mitochondria [29], particularly under pathological conditions [21].”

What the sources say

• Not checked yetcites [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
• 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

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

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

In the paper

“This pathway's activation improves protein folding, inhibits protein synthesis to alleviate ER stress, and removes damaged proteins.”

In the paper

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

In the paper

“This difference can be explained because MFN1 has a greater GTPase membrane tethering activity [61].”

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

In the paper

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

In the paper

“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).”

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

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

In the paper

“Thus, mitochondrial integrity and function need to be highly regulated.”

In the paper

“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].”

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

“Mitoproteases do not only monitor mitochondrial protein quality, but also they can decide mitochondrial fate.”

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Mitochondrial dysfunction has been linked to several human diseases, like specific genetic defects, neurodegenerative and age-related diseases like aging sarcopenia, diabetes, and obesity.”

In the paper

“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].”

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
• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

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

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“Mitochondrial fusion leads to elongated organelles, which expand the mitochondrial network and its interconnectivity [32].”

What the sources say

• 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

“It starts with the tethering of two adjacent mitochondria, continues with the fusion of OMM, and concludes with IMM fusion.”

In the paper

“Mitochondria have their genome, transcription, and translation machinery [33].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Moreover, unfolded IMS proteins can exit the IMS through the TOM translocase, which is the same route used for import [40].”

What the sources say

• 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

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

In the paper

“Although DRP1 can tubulate the membranes, it cannot complete membrane scission [84].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 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

“OPA1-dependent mitochondrial fusion needs Mfn1 [73] as well as balanced OPA1S and OPA1L forms.”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“However, mammals lack a homolog of the fission protein FtsZ [99].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• 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 [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“On the contrary, silencing MFF generates elongated mitochondria and DRP1 cytosolic distribution [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 [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

“Under stress conditions, hyperacetylation of OPA1 reduces its GTPase activity while SIRT3-dependent deacetylation increases OPA1 GTPase activity [79].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

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

“Indeed, the GTPase Dynamin 2 (DYN2) assembles in the DRP1-mediated mitochondrial constriction neck to drive mitochondrial scission [85].”

What the sources say

• Not checked yetcites [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

In the paper

“The mechanism which drives IMM constriction are not elucidated, but the requirement of MCU and OMA1-induced OPA1S has been shown [102, 103].”

What the sources say

• Not checked yetcites [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 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

“OPA1 deletion leads to mitochondrial fragmentation, whereas OPA1 overexpression induces mitochondrial elongation [73].”

What the sources say

• Not checked yetcites [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

In the paper

“In mammals, there are no orthologues for MDV1 and Cav 4, and recent evidence suggests that Fis1 is not required for fission [89, 90].”

What the sources say

• Not checked yetcites [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 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

In the paper

“On the contrary, the complete conversion of OPA1L into OPA1S inhibits fusion and increases mitochondrial fission [74, 76].”

What the sources say

• Not checked yetcites [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 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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

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
• Not checked yetcites [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

In the paper

“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.”

In the paper

“Moreover, p97/VCP deficiency resulted in the accumulation of numerous vesicular bodies, autophagy impairment, and altered myofibrillar organization, causing a severe myopathy.”

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

“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).”

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

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“mitochondrial fusion in skeletal muscle is necessary to adapt to the cell's specific functional needs and support skeletal muscle myofibers contractile function [54].”

What the sources say

• Not checked yetcites [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

In the paper

“In agreement, double deletion of Yme1L1 and OMA1, specifically in the heart, restored mitochondrial morphology and rescued cardiac function [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

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

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

“Mechanistically, YME1L ablation in cardiomyocytes activates OMA1 and promotes OPA1 processing and mitochondrial fragmentation, which causes heart failure [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

“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].”

What the sources say

• 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

“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].”

What the sources say

• Not checked yetcites [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

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Loss-of-function mutations in MiD49 cause severe myopathy in humans, with Complex I and Complex IV deficiency in muscle [206].”

What the sources say

• Not checked yetcites [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

In the paper

“Impairment of fission leads to the disruption of selective mitochondrial autophagic degradation, followed by dysfunctional organelles accumulation [58, 196–200].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 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

“Constitutive DRP1 knockout animals are embryonically lethal, demonstrating that the fission machinery is critical for tissue development and function [208, 209].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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