Polycomb Repressive Complex 1 and USP16 localize to the mitochondrion and influence its function.

Abstract

Polycomb Repressive Complex 1 (PRC1) represses gene expression by ubiquitinating histone H2A or physically compacting chromatin. USP16, one of the histone H2A deubiquitinases, antagonizes PRC1-mediated H2A ubiquitination (H2Aub). Here, we report that both PRC1 and USP16 are also localized in mitochondria and influence mitochondrial function directly. Our findings are based on immunofluorescence and proximity ligation assays, cell fractionation, and biochemical analyses of isolated or affinity-purified mitochondria. We further showed that PRC1 and USP16 function with the ubiquitin pathway. Auxin-induced, mitochondria-specific depletion of the PRC1 subunit RING2 altered the ubiquitination status of mitochondrial proteins, including H2Aub. Disruption of PRC1, either through double knockout (KO) of <i>RING1</i> and <i>RING2</i> or through mitochondria-specific deletion of RING2 in the <i>RING1</i> KO background, caused profound alterations in mitochondrial proteome and led to disturbances in mitochondrial integrity and impaired respiratory function. Thus, in addition to their canonical functions in the nucleus, PRC1 and USP16 also translocate into mitochondria and directly impact mitochondrial integrity and function.