P107 mediated mitochondrial function controls muscle stem cell proliferative fates

Debasmita Bhattacharya,Anthony Scimè,Vicky Shah,Oreoluwa Oresajo

doi:10.1038/s41467-021-26176-0

Abstract

Muscle diseases and aging are associated with impaired myogenic stem cell self-renewal and fewer proliferating progenitors (MPs). Importantly, distinct metabolic states induced by glycolysis or oxidative phosphorylation have been connected to MP proliferation and differentiation. However, how these energy-provisioning mechanisms cooperate remain obscure. Herein, we describe a mechanism by which mitochondrial-localized transcriptional co-repressor p107 regulates MP proliferation. We show p107 directly interacts with the mitochondrial DNA, repressing mitochondrial-encoded gene transcription. This reduces ATP production by limiting electron transport chain complex formation. ATP output, controlled by the mitochondrial function of p107, is directly associated with the cell cycle rate. Sirt1 activity, dependent on the cytoplasmic glycolysis product NAD+, directly interacts with p107, impeding its mitochondrial localization. The metabolic control of MP proliferation, driven by p107 mitochondrial function, establishes a cell cycle paradigm that might extend to other dividing cell types.

Highlights

proliferation based on Sirt[1] activity
active interacting with p107 preventing its mitochondrial localization
free to relocate to the mitochondria

Summary

G Ga G Ga

There was significantly less mitochondrial-encoded gene expression in Sirt1dn cells grown in 5.5 mM glucose compared to Sirt1fl (Compare Fig. 4c, Supplementary Fig. 22) Together, these results suggest that p107 is influenced directly by Sirt[1] activity to localize within the cytoplasm, de-repressing mitochondrial gene expression and increasing ATP generation capacity. The muscles from p107KO mice treated or untreated with ox showed no difference in proliferating MPs (Fig. 5o, p, Supplementary Fig. 30) These results suggest that p107 mitochondrial function controls cell cycle rate by regulating ETC complex formation in a Sirt[1] dependent manner (Fig. 6)

Discussion

Findings

Methods