Mitochondria in muscle stem cell biology: gatekeepers of fate, function, and regeneration

Muscle stem cells (MuSCs) are essential for skeletal muscle regeneration and maintenance of tissue homeostasis. However, their regenerative capacity declines with aging and in several pathological conditions, including neuromuscular diseases, cancer cachexia, sepsis, and metabolic disorders. Increasing evidence has identified mitochondria as key regulators of MuSC behavior, influencing quiescence, activation, self-renewal, and differentiation during myogenesis. In addition to their role in energy production, mitochondria function as metabolic and signaling hubs that integrate cellular and environmental cues to control stem cell fate decisions. This review summarizes current knowledge on the role of mitochondria in MuSC biology, including the contribution of mitochondrial bioenergetics and metabolic signaling to MuSC state transitions, the importance of mitochondrial network dynamics in regulating stem cell function, and the role of mitochondrial quality control mechanisms such as mitophagy and selective mitochondrial inheritance. We further discuss how mitochondrial dysfunction contributes to impaired MuSC function in aging and muscle-wasting conditions and highlight potential therapeutic strategies targeting mitochondrial pathways to improve muscle regeneration.