COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function

ABSTRACT: Reversible acetylation of mitochondrial proteins is a regulatory mechanism central to adaptive metabolic responses. Yet, how such functionally relevant protein acetylation is achieved remains unexplored. Here, we reveal an unprecedented role of the MYST family lysine acetyltransferase MOF in energy metabolism via mitochondrial protein acetylation. Loss of MOF-KANSL complex members led to mitochondrial defects including fragmentation, reduced cristae density and impaired mitochondrial electron transport chain (mtETC) complex IV (CIV) integrity in primary mouse embryonic fibroblasts. We demonstrate COX17, a CIV assembly factor, as a bona fide acetylation target of MOF. Loss of COX17 or expression of its non-acetylatable mutant phenocopied the mitochondrial defects observed upon MOF depletion. The acetylation-mimetic COX17 rescues these defects and maintains CIV activity even in the absence of MOF, suggesting an activatory role of mtETC protein acetylation. Fibroblasts from MOF syndrome patients with intellectual disability also revealed respiratory defects that could be restored by alternative oxidase, acetylation-mimetic COX17 or mitochondrially targeted MOF. Overall, our findings highlight the critical role of MOF-KANSL complex in mitochondrial physiology and provide new insights into MOF syndrome.​

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE199009 | GEO | 2023/10/09

REPOSITORIES: GEO