Contribution of Mitochondrial Calcium Uptake to Intracellular Calcium Homeostasis Studied with Organelle-Targetted Probes in Skeletal Muscle Fibers

Voltage dependent anion channel 2 (VDAC2) is a mitochondrial outer membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in cellular calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. Previous literature suggests that improving mitochondrial calcium uptake via VDAC2 rescues arrhythmia phenotypes in genetic models of impaired cellular calcium signaling. However, the direct role of VDAC2 in intracellular calcium signaling and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac-specific deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium during development causes severe impairment in excitation-contraction coupling by reducing mitochondrial calcium uptake (n=3, p<0.05) and thereby impairing intracellular calcium signaling. VDAC2 knock-out mice showed a significant reduction in RYR-mediated calcium release (F/F 0 ) and rate of calcium uptake by SERCA2a [tau(msec)] compared to control mice (N=3, WT=54, KO=38, p<0.0001 (F/F 0 ) and p<0.05 (tau)). We also observed adverse cardiac remodeling which progressed to severe dilated cardiomyopathy and death (N=6, p<0.0001). Reintroducing VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype evident from improvement in ejection fraction and fractional shortening (n=3, p<0.05). Improving mitochondrial calcium uptake via VDAC2 using a VDAC2 agonist efsevin, increased cardiac contractile force in a mouse model of pressure-overload induced heart failure (N=8, n=22, p<0.05). In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing mitochondrial and cellular calcium signaling. Through this role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.

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MICU3 regulates mitochondrial Ca2+-dependent antioxidant response in skeletal muscle aging

Cell Death and Disease ◽

10.1038/s41419-021-04400-5 ◽

2021 ◽

Vol 12 (12) ◽

Author(s):

Yun-Fei Yang ◽

Wu Yang ◽

Zhi-Yin Liao ◽

Yong-Xin Wu ◽

Zhen Fan ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Calcium Uptake ◽

Mitochondrial Calcium ◽

Muscle Aging ◽

Skeletal Muscle Aging ◽

And Function ◽

Mitochondrial Calcium Uptake

AbstractAge-related loss of skeletal muscle mass and function, termed sarcopenia, could impair the quality of life in the elderly. The mechanisms involved in skeletal muscle aging are intricate and largely unknown. However, more and more evidence demonstrated that mitochondrial dysfunction and apoptosis also play an important role in skeletal muscle aging. Recent studies have shown that mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium affects skeletal muscle mass and function by affecting mitochondrial function. During aging, we observed downregulated expression of mitochondrial calcium uptake family member3 (MICU3) in skeletal muscle, a regulator of MCU, which resulted in a significant reduction in mitochondrial calcium uptake. However, the role of MICU3 in skeletal muscle aging remains poorly understood. Therefore, we investigated the effect of MICU3 on the skeletal muscle of aged mice and senescent C2C12 cells induced by d-gal. Downregulation of MICU3 was associated with decreased myogenesis but increased oxidative stress and apoptosis. Reconstitution of MICU3 enhanced antioxidants, prevented the accumulation of mitochondrial ROS, decreased apoptosis, and increased myogenesis. These findings indicate that MICU3 might promote mitochondrial Ca2+ homeostasis and function, attenuate oxidative stress and apoptosis, and restore skeletal muscle mass and function. Therefore, MICU3 may be a potential therapeutic target in skeletal muscle aging.

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Heat Stress Impairs Intracellular Calcium Homeostasis In Rat Skeletal Muscle In Vivo

Medicine & Science in Sports & Exercise ◽

10.1249/01.mss.0000493742.07889.fe ◽

2014 ◽

Vol 46 ◽

pp. 187-188

Author(s):

Tomosada Ishiguro ◽

Hiroaki Eshima ◽

David C. Poole ◽

Yutaka Kano

Keyword(s):

Skeletal Muscle ◽

Heat Stress ◽

Intracellular Calcium ◽

Calcium Homeostasis ◽

Rat Skeletal Muscle ◽

Intracellular Calcium Homeostasis

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Parvalbumin affects skeletal muscle trophism through modulation of mitochondrial calcium uptake

Cell Reports ◽

10.1016/j.celrep.2021.109087 ◽

2021 ◽

Vol 35 (5) ◽

pp. 109087

Author(s):

Gaia Butera ◽

Denis Vecellio Reane ◽

Marta Canato ◽

Laura Pietrangelo ◽

Simona Boncompagni ◽

...

Keyword(s):

Skeletal Muscle ◽

Calcium Uptake ◽

Mitochondrial Calcium ◽

Mitochondrial Calcium Uptake

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Mitochondrial calcium uptake regulates tumour progression in embryonal rhabdomyosarcoma

10.1101/2021.11.10.468020 ◽

2021 ◽

Author(s):

Reshma Taneja ◽

Hsin Yao Chiu ◽

Amos Hong Pheng Loh

Keyword(s):

Calcium Homeostasis ◽

Calcium Uptake ◽

Cellular Proliferation ◽

Myogenic Differentiation ◽

Tumour Progression ◽

Embryonal Rhabdomyosarcoma ◽

Mitochondrial Calcium ◽

Mitochondrial Calcium Uptake

Embryonal rhabdomyosarcoma (ERMS) is characterized by a failure of cells to complete skeletal muscle differentiation. Although ERMS cells are vulnerable to oxidative stress, the relevance of mitochondrial calcium homeostasis in oncogenesis is unclear. Here, we show that ERMS cell lines as well as primary tumours exhibit elevated expression of the Mitochondrial Calcium Uniporter (MCU). MCU knockdown resulted in impaired mitochondrial calcium uptake and a reduction in mitochondrial reactive oxygen species (mROS) levels. Phenotypically, MCU knockdown cells exhibited reduced cellular proliferation and motility, with an increased propensity to differentiate in vitro and in vivo. RNA-sequencing of MCU knockdown cells revealed a significant reduction in genes involved in TGF? signalling that play prominent roles in oncogenesis and inhibition of myogenic differentiation. Interestingly, modulation of mROS production impacted TGF? signalling. Our study elucidates mechanisms by which mitochondrial calcium dysregulation promotes tumour progression and suggests that targeting the MCU complex to restore mitochondrial calcium homeostasis could be a therapeutic avenue in ERMS.

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