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<p>Mitochondrial Ca²⁺ dysregulation is a central pathogenic event in skeletal muscle disorders, yet the dichotomy between overload and deficiency is often overlooked. This review summarizes mechanisms governing mitochondrial Ca²⁺ transport and sarcoplasmic reticulum-mitochondria communication. We examine prerequisites of Ca²⁺ overload, including RyR1/SERCA dysfunction and mitochondrial calcium uniporter (MCU) complex remodeling, leading to suppressed ATP synthesis, reactive oxygen species overproduction, and necrosis. Conversely, we address mitochondrial Ca²⁺ deficiency in aging, sarcopenia, and diabetes, resulting from altered MCU stoichiometry and reduced organelle tethering, causing metabolic inflexibility and impaired antioxidant defense. Additionally, therapeutic strategies limiting Ca²⁺ overload and prospects of pharmacological MCU activation to enhance bioenergetics in sarcopenia are discussed.</p>

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The two faces of mitochondrial Ca2+ dysregulation in skeletal muscle: overload and deficiency

  • 期刊论文

  • 发表日期：

    2026年6月23日

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  • Mikhail V. Dubinin,
  • Konstantin N. Belosludtsev

摘要

Mitochondrial Ca²⁺ dysregulation is a central pathogenic event in skeletal muscle disorders, yet the dichotomy between overload and deficiency is often overlooked. This review summarizes mechanisms governing mitochondrial Ca²⁺ transport and sarcoplasmic reticulum-mitochondria communication. We examine prerequisites of Ca²⁺ overload, including RyR1/SERCA dysfunction and mitochondrial calcium uniporter (MCU) complex remodeling, leading to suppressed ATP synthesis, reactive oxygen species overproduction, and necrosis. Conversely, we address mitochondrial Ca²⁺ deficiency in aging, sarcopenia, and diabetes, resulting from altered MCU stoichiometry and reduced organelle tethering, causing metabolic inflexibility and impaired antioxidant defense. Additionally, therapeutic strategies limiting Ca²⁺ overload and prospects of pharmacological MCU activation to enhance bioenergetics in sarcopenia are discussed.