The pyruvate dehydrogenase complex regulates mitochondrial matrix protein phosphorylation and mitophagic selectivity, independent of its catalytic activity

Mitophagy, or the autophagic degradation of mitochondria, is an important housekeeping function of eukaryotic cells that prevents the accumulation of defective mitochondria due to oxidative damage and spontaneous mutations. The culling of defective mitochondria is thought to delay the onset of aging symptoms, and defects in mitophagy have been linked to late onset disorders such as Parkinson’s disease and type II diabetes. We previously demonstrated that different mitochondrial matrix proteins undergo mitophagy at different rates, and that mitochondrial matrix protein phosphorylation and dephosphorylation can generate a segregation principle that would couple with mitochondrial fission and fusion dynamics to selectively degrade sub-sets of mitochondrial proteins. We now demonstrate a role for the pyruvate dehydrogenase complex (PDC) as a signaling nexus in this regulatory network. We demonstrate that the PDC controls the activities of its cognate kinases and phosphatases towards other mitochondrial matrix proteins, and that this novel function can be uncoupled from the pyruvate dehydrogenase catalytic function itself. Our data support a model where the PDC functions in a structural role to allosterically regulate its associated kinases and phosphatases towards ‘third party’ proteins in the mitochondrial matrix, suggesting a possible regulatory link between the levels of central mitochondrial metabolites and the regulation of mitophagic selectivity.