p107 mediated mitochondrial function controls muscle stem cell proliferative fates

Abstract

Muscle wasting diseases and aging are associated with impaired myogenic stem cell selfrenewal and a diminished number of their proliferating progenitors (MPs). Importantly, distinct metabolic states govern MP proliferation and differentiation. Central to this is the regulation between glycolysis and oxidative phosphorylation (Oxphos). However, the mechanisms that connect these energy provisioning centers to control cell behaviour remain obscure. Herein, our results reveal a mechanism by which mitochondrial-localized transcriptional co-repressor p107 governs MP proliferation. We found p107 directly interacts at the mitochondrial DNA promoter, repressing mitochondrial-encoded genes. This reduces mitochondrial ATP generation, by limiting the electron transport chain complex formation. Importantly, the amount of ATP generated by the mitochondrial function of p107 is directly associated to the cell cycle rate. Sirt1, whose activity is dependent on the cytoplasmic by-product of glycolysis, NAD+, directly interacts with p107 impeding its mitochondrial localization and function. The metabolic control of cell cycle, driven by differential p107 mitochondrial function, establishes a new paradigm to manipulate muscle cell proliferative fates that is likely to extend to most other dividing cell types.