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

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.