The Role of Mitochondrial Dynamics in Muscle Stem Cell Quiescence and Cell Cycle Re-Entry

Abstract

Balanced stem cell fate decisions are essential for the maintenance and regeneration of tissues across the lifespan. The mitochondrial fusion protein OPA1 and mitochondrial shape changes are essential contributors to balanced fate decisions, however the full mechanistic scope of their signalling abilities are not fully known. Here, using OPA1-deficient and OPA1-overexpressing muscle stem cells (MuSCs), we show that mitochondrial shape changes alter the metabolome of MuSCs. These OPA1-regulated metabolites possess distinct abilities to alter MuSC progression and fate. Furthermore, OPA1 expression and mitochondrial shape alters the ratio of alpha-ketoglutarate (aKG) to succinate, and this ratio dictates the decisions to self-renew or commit. Manipulation of this ratio in vitro is sufficient to alter the fate of MuSCs by modifying mitochondrial shape and altering the expression of key stemness and myogenic genes. In addition, we find that committed and self-renewed MuSCs have opposing gene expression profiles indicative of differential [aKG]:[succinate] ratios. Lastly, in OPA1-deficient mice, in vivo restoration of this ratio prevents MuSC depletion and preserves the stem cell pool after injury and decreases precocious commitment and differentiation. Our studies present a novel role for mitochondrial shape as a signalling mechanism to guide MuSC progression and fate.