PT  - JOURNAL ARTICLE
AU  - Debasmita Bhattacharya
AU  - Oreoluwa Oresajo
AU  - Anthony Scimè
TI  - Sirt1 mediated regulation of p107 mitochondrial function controls muscle stem cell proliferative fates
AID  - 10.1101/2020.09.29.317693
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.29.317693
4099  - http://biorxiv.org/content/early/2020/09/30/2020.09.29.317693.short
4100  - http://biorxiv.org/content/early/2020/09/30/2020.09.29.317693.full
AB  - Muscle wasting diseases and aging are associated with impaired myogenic stem cell self-renewal and a diminished number of their proliferating and differentiating committed muscle progenitor cells (MPs). Importantly, distinct metabolic states govern how MPs proliferate and differentiate. Central to this is the regulation of energy generation between glycolysis in the cytoplasm and oxidative phosphorylation (Oxphos) in the mitochondria. 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 proliferative capacity, under the control of NAD+ dependent Sirt1 deacetylase. We found p107 directly interacts at the mitochondrial DNA promoter leading to repression of mitochondrial-encoded genes. This reduces the mitochondrial ATP generation capacity, 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 in vivo and in vitro. In vivo, p107 genetically deleted MPs had a faster proliferative capacity, whereas forced expression of p107 in the mitochondria blocked cell cycle progression. Sirt1, whose activity is dependent on the cytoplasmic by-product of glycolysis, NAD+, directly interacts with p107 impeding its mitochondrial localization and function. Deletion of Sirt1 increased p107 mitochondrial localization, decreased MP mitochondrial Oxphos generation, concomitant with dampened cell cycle progression. Increasing the activity of Sirt1 had the opposite effect on p107 function. This metabolic control of cell cycle progression, driven by differential p107 mitochondrial function based on Sirt1 activity, establishes a new paradigm to manipulate muscle cell proliferative fates that is likely to extend to most other dividing cell types.Competing Interest StatementThe authors have declared no competing interest.