A novel phosphorylation cascade regulates mitophagic selectivity from within the mitochondrial matrix

Abstract

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. We now find that dynamic mitochondrial matrix protein phosphorylation and dephosphorylation can generate a segregation principle that would couple with mitochondrial fission and fusion to selectively degrade sub-sets of mitochondrial proteins on the basis of differential covalent modification. Our data support a model wherein differences in protein-protein interactions between differentially phosphorylated proteins of the same species can drive a microscopic phase separation which, coupled with fusion-fission dynamics, may account for the observed selectivity.