A SIRT7-Dependent Acetylation Switch of GABPβ1 Controls Mitochondrial Function

Mitochondrial activity is controlled by proteins encoded by both nuclear and mitochondrial DNA. Here, we identify Sirt7 as a crucial regulator of mitochondrial homeostasis. Sirt7 deficiency in mice induces multisystemic mitochondrial dysfunction, which is reflected by increased blood lactate levels, reduced exercise performance, cardiac dysfunction, hepatic microvesicular steatosis, and age-related hearing loss. This link between SIRT7 and mitochondrial function is translatable in humans, where SIRT7 overexpression rescues the mitochondrial functional defect in fibroblasts with a mutation in NDUFSI. These wide-ranging effects of SIRT7 on mitochondrial homeostasis are the consequence of the deacetylation of distinct lysine residues located in the hetero- and homodimerization domains of GABPβ1, a master regulator of nuclear-encoded mitochondrial genes. SIRT7-mediated deacetylation of GABPβ1 facilitates complex formation with GABPα and the transcriptional activation of the GABPα/GABPβ heterotetramer. Altogether, these data suggest that SIRT7 is a dynamic nuclear regulator of mitochondrial function through its impact on GABPβ1 function. [Display omitted] •Loss of Sirt7 function reduces the expression of nDNA-encoded mitochondrial genes•Sirt7−/− mice display pleiotropic features of mitochondrial dysfunction•SIRT7 stabilizes and activates the GABPα/GABPβ complex via deacetylation of GABPβ1•The GABPβ1 acetylation status is dynamically regulated by feeding and aging Sirtuins are NAD-dependent deacetylases that regulate numerous metabolic pathways. Ryu et al. identify Sirt7 deacetylation of GABPβ1, a master regulator of nuclear-encoded mitochondrial genes, as essential for maintenance of mitochondrial function in multiple tissues. SIRT7 overexpression rescued mitochondrial defects in NDUFS1-deficient patient fibroblasts, highlighting a possible therapeutic approach for mitochondrial dysfunction.