Role of Mitofusin-2 in mitochondrial localization and calcium uptake in skeletal muscle

Ainbinder, Alina; Boncompagni, Simona; Protasi, Feliciano; Dirksen, Robert T.

doi:10.1016/j.ceca.2014.11.002

Cited by 99 publications

(106 citation statements)

References 42 publications

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“…To sum up: (1) (Baylor and Hollingworth 2007;Williams et al 2013), and this agrees with results obtained with repeated contractions of mouse soleus muscle fibers (Bruton et al 2003a). Conversely, mitochondrial Ca 2þ uptake appeared to affect tetanic [Ca 2þ ] i in muscle fibers of Xenopus frogs , and the decreased mitochondrial Ca 2þ uptake during contractions was accompanied by in-creased [Ca 2þ ] i transients in mouse muscle fibers exposed to short-term knockdown of mitofusin-2, which participates in mitochondrial fusion (Ainbinder et al 2015).…”

Section: Mitochondrial Ca 2þ Uptakesupporting

confidence: 82%

“…Accordingly, MCU is regulated by several inner mitochondrial membrane proteins, which either stimulate or inhibit Ca 2þ entry (Williams et al 2015). The existence of an intricate regulation of [Ca 2þ ] mito is illustrated by studies with repeated tetanic contractions of mouse wild-type skeletal muscle fibers, where the repeated large increases in [Ca 2þ ] i during contractions were accompanied by [Ca 2þ ] mito remaining virtually constant Bruton et al 2003b;Aydin et al 2009), increasing substantially in mitochondria close to the surface (Bruton et al 2003a), or increasing substantially and globally (Rossi et al 2011;Ainbinder et al 2015).…”

Section: Mitochondrial Ca 2þ Uptakementioning

confidence: 99%

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Molecular Basis for Exercise-Induced Fatigue: The Importance of Strictly Controlled Cellular Ca²⁺Handling

Cheng

Place

Westerblad

2017

Cold Spring Harb Perspect Med

100

112

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The contractile function of skeletal muscle declines during intense or prolonged physical exercise, that is, fatigue develops. Skeletal muscle fibers fatigue acutely during highly intense exercise when they have to rely on anaerobic metabolism. Early stages of fatigue involve impaired myofibrillar function, whereas decreased Ca 2þ release from the sarcoplasmic reticulum (SR) becomes more important in later stages. SR Ca 2þ release can also become reduced with more prolonged, lower intensity exercise, and it is then related to glycogen depletion. Increased reactive oxygen/nitrogen species can cause long-lasting impairments in SR Ca 2þ release resulting in a prolonged force depression after exercise. In this article, we discuss molecular and cellular mechanisms of the above fatigue-induced changes, with special focus on multiple mechanisms to decrease SR Ca 2þ release to avoid energy depletion and preserve muscle fiber integrity. We also discuss fatigue-related effects of exerciseinduced Ca 2þ fluxes over the sarcolemma and between the cytoplasm and mitochondria.T he contractile function of skeletal muscle fibers declines during intense or prolonged physical exercise, that is, fatigue develops. Within the muscle fibers, fatigue is generally related to increased energy demands, in which effective ATP resynthesis is needed to match the dramatically increased ATP consumption during contractions. In contracting muscle fibers, ATP is mainly consumed by the molecular motorsthe actomyosin cross-bridges; ion pumps-the sarcoplasmic reticulum (SR) Ca 2þ -pumps (SERCA); and, to a minor degree, the sarcolemmal Na þ -K þ -pumps. Adequate ATP delivery to these ATP-consuming proteins is essential for normal cell function and integrity, because depletion of ATP would have devastating consequences: constantly attached, noncycling crossbridges and rigor development; insufficient SR Ca 2þ pumping leading to an uncontrolled increase in the free cystolic [Ca 2þ ] ([Ca 2þ ] i ); and inadequate maintenance of Na þ and K þ gradients over the sarcolemma resulting in impaired action potential propagation and muscle fibers eventually becoming inexcitable. Obviously, mechanisms to prevent these catastrophic consequences of ATP depletion exist within the

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Section: Mitochondrial Ca 2þ Uptakesupporting

confidence: 82%

Section: Mitochondrial Ca 2þ Uptakementioning

confidence: 99%

Molecular Basis for Exercise-Induced Fatigue: The Importance of Strictly Controlled Cellular Ca²⁺Handling

Cheng

Place

Westerblad

2017

Cold Spring Harb Perspect Med

100

112

View full text Add to dashboard Cite

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“…function as a tether, bridging the SER (45, 46) and mitochondria, thereby facilitating interorganelle Ca 2ϩ cross-talk (47). Further data showing superinduction of Mfn 2 upon iBATablation along with cold-mediated up-regulation of VDAC 1 may suggest increased Ca 2ϩ cross-talk between the SER and mitochondria plays a crucial role in muscle-based NST.…”

Section: Discussionmentioning

confidence: 95%

Increased Reliance on Muscle-based Thermogenesis upon Acute Minimization of Brown Adipose Tissue Function

Bal

Maurya

Singh

et al. 2016

Journal of Biological Chemistry

102

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Skeletal muscle has been suggested as a site of nonshivering thermogenesis (NST) besides brown adipose tissue (BAT). Studies in birds, which do not contain BAT, have demonstrated the importance of skeletal muscle-based NST. However, musclebased NST in mammals remains poorly characterized. We recently reported that sarco/endoplasmic reticulum Ca 2؉ cycling and that its regulation by SLN can be the basis for muscle NST. Because of the dominant role of BAT-mediated thermogenesis in rodents, the role of muscle-based NST is less obvious. In this study, we investigated whether muscle will become an important site of NST when BAT function is conditionally minimized in mice. We surgically removed interscapular BAT (iBAT, which constitutes ϳ70% of total BAT) and exposed the mice to prolonged cold (4°C) for 9 days. The iBAT-ablated mice were able to maintain optimal body temperature (ϳ35-37°C) during the entire period of cold exposure. After 4 days in the cold, both sham controls and iBAT-ablated mice stopped shivering and resumed routine physical activity, indicating that they are cold-adapted. The iBAT-ablated mice showed higher oxygen consumption and decreased body weight and fat mass, suggesting an increased energy cost of cold adaptation. The skeletal muscles in these mice underwent extensive remodeling of both the sarcoplasmic reticulum and mitochondria, including alteration in the expression of key components of Ca 2؉ handling and mitochondrial metabolism. These changes, along with increased sarcolipin expression, provide evidence for the recruitment of NST in skeletal muscle. These studies collectively suggest that skeletal muscle becomes the major site of NST when BAT activity is minimized.

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“…The other role is to control mitochondrial dynamics via fission by targeting of Drp1 (15,16) and via motility by targeting of Miro proteins (17)(18)(19) in the cytoplasm. In some striated muscles, including mammalian myocardium, mitochondria are strategically located for uptake and sensing of small amount of Ca 2+ during its release from the adjoining SR (6,20,21). This makes mitochondria particularly responsive to changes in Ca 2+ homeostasis.…”

Section: Camentioning

confidence: 99%

“…Obviously, neither extreme view applies perfectly to all cells, tissues, and functional conditions. In differentiated skeletal and cardiac muscle, mitochondria are stabilized in a stereotyped positioning relative to myofibrils mostly because their movements are restricted by the narrow spaces between the myofibrils and also because they are specifically tethered, perhaps via mitofusin-2 to the membrane systems, mostly to the sarcoplasmic reticulum (SR) (5)(6)(7)(8). Exchange of matrix content, DNA, and proteins and segregation of damaged mitochondrial components are needed for maintaining mitochondrial and cell functions (9,10).…”

mentioning

confidence: 99%

Increased mitochondrial nanotunneling activity, induced by calcium imbalance, affects intermitochondrial matrix exchanges

Lavorato

Iyer

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Exchanges of matrix contents are essential to the maintenance of mitochondria. Cardiac mitochondrial exchange matrix content in two ways: by direct contact with neighboring mitochondria and over longer distances. The latter mode is supported by thin tubular protrusions, called nanotunnels, that contact other mitochondria at relatively long distances. Here, we report that cardiac myocytes of heterozygous mice carrying a catecholaminergic polymorphic ventricular tachycardia-linked RyR2 mutation (A4860G) show a unique and unusual mitochondrial response: a significantly increased frequency of nanotunnel extensions. The mutation induces Ca 2+ imbalance by depressing RyR2 channel activity during excitation-contraction coupling, resulting in random bursts of Ca 2+ release probably due to Ca 2+ overload in the sarcoplasmic reticulum. We took advantage of the increased nanotunnel frequency in RyR2 A4860G+/− cardiomyocytes to investigate and accurately define the ultrastructure of these mitochondrial extensions and to reconstruct the overall 3D distribution of nanotunnels using electron tomography. Additionally, to define the effects of communication via nanotunnels, we evaluated the intermitochondrial exchanges of matrix-targeted soluble fluorescent proteins, mtDsRed and photoactivable mtPA-GFP, in isolated cardiomyocytes by confocal microscopy. A direct comparison between exchanges occurring at short and long distances directly demonstrates that communication via nanotunnels is slower. mitochondria | nanotunnels | CPVT | RyR2 | mitochondrial dynamics

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Role of Mitofusin-2 in mitochondrial localization and calcium uptake in skeletal muscle

Cited by 99 publications

References 42 publications

Molecular Basis for Exercise-Induced Fatigue: The Importance of Strictly Controlled Cellular Ca²⁺Handling

Molecular Basis for Exercise-Induced Fatigue: The Importance of Strictly Controlled Cellular Ca²⁺Handling

Increased Reliance on Muscle-based Thermogenesis upon Acute Minimization of Brown Adipose Tissue Function

Increased mitochondrial nanotunneling activity, induced by calcium imbalance, affects intermitochondrial matrix exchanges

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Role of Mitofusin-2 in mitochondrial localization and calcium uptake in skeletal muscle

Cited by 99 publications

References 42 publications

Molecular Basis for Exercise-Induced Fatigue: The Importance of Strictly Controlled Cellular Ca2+Handling

Molecular Basis for Exercise-Induced Fatigue: The Importance of Strictly Controlled Cellular Ca2+Handling

Increased Reliance on Muscle-based Thermogenesis upon Acute Minimization of Brown Adipose Tissue Function

Increased mitochondrial nanotunneling activity, induced by calcium imbalance, affects intermitochondrial matrix exchanges

Contact Info

Product

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Molecular Basis for Exercise-Induced Fatigue: The Importance of Strictly Controlled Cellular Ca²⁺Handling

Molecular Basis for Exercise-Induced Fatigue: The Importance of Strictly Controlled Cellular Ca²⁺Handling