The nucleus is a common quality control destination for failed mitochondrial import substrates Viplendra P.S. Shakya1, William Barbeau1, Christina Knutson1 and Adam L. Hughes1 1Department of Biochemistry, University of Utah School of Medicine
Mitochondria contain ~1,000 proteins in yeast, and the vast majority (~99%) of these proteins are encoded in the nucleus, translated in the cytoplasm, and imported into mitochondria post- or co-translationally. Import of most mitochondrial proteins require the mitochondrial inner membrane potential, which is generated by the electron transport chain. Thus, under conditions of mitochondrial impairment, which is common during aging and disease states, hundreds of mitochondrial-destined precursor proteins fail to be imported. It was recently shown that the accumulation of mitochondrial precursor proteins in import deficient cells leads to significant proteotoxicity, termed mitochondrial precursor overaccumulation stress (mPOS). Despite the prevalence of this stress in cells, we have a limited understanding of the systems that operate to mitigate toxicity of non-imported mitochondrial proteins. To address this knowledge gap, we recently conducted a series of microscopy-based screens in yeast to determine the fate of non-imported mitochondrial proteins. Our studies uncovered five distinct fates for mitochondrial proteins that fail to be imported, and identified the nucleus as a common destination for non-imported mitochondrial precursors. Our current results suggest that non-imported mitochondrial proteins are routed to the nucleus for proteasome-dependent destruction by the well-characterized nuclear protein quality control machinery, and that loss of this machinery leads to sequestration of non-imported mitochondrial proteins into previously defined nuclear-associated protein aggregates, referred to as JUNQ or INQ. Overall, these studies have uncovered an unexpected role for the nuclear protein quality control machinery in the degradation of non-imported mitochondrial precursor proteins, and suggest that non-imported precursors are handled by a diverse array of quality control mechanisms. Future studies are aimed at dissecting the machinery involved in other, non-nuclear quality control pathways for mitochondrial precursors, and identifying protein features that direct non-imported proteins toward a given fate.
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