Mitochondrial inheritance and quality control

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Protein homeostasis, or proteostasis, relies on precise control of protein synthesis, folding and degradation. Proteostatic errors lead to protein aggregates, which are toxic and linked to neurodegenerative, cardiovascular, muscular and metabolic disorders, and to premature aging. The ER and mitochondria are major sites for protein folding and are supported by quality control mechanisms that correct protein folding or eliminate proteins or organelles that are damaged beyond repair. ER-associated degradation (ERAD) and mitochondria-associated degradation (MAD) are functionally and mechanistically related mechanisms. In both, misfolded proteins are identified, ubiquitinated, extracted from organelles and degraded by the proteasome. However, both pathways have limitations. Previous studies suggested that MAD proteostasis was restricted to mitochondrial outer mem- brane (OM) proteins, <10% of mitochondrial proteins. Moreover, MAD and ERAD are inherently low-throughput because they act on individual proteins. This limitation is a particular concern for ER, where 1/3 of all proteins in the cell undergo folding, and protein entry into ER occurs at rates of 0.1-1 million proteins/minute. In the last funding period, we found that MAD functions in proteostatic control of mitochondrial matrix and inner membrane proteins. Consistent with this, we found that MAD and not chaperones, proteases or autophagy proteins, plays a major role in mitochondrial and cellular fitness in a model for aging and that loss of MAD function results in premature aging. We also reconstituted retrotranslocation of MAD substrates from the matrix in vitro and identi- fied a role for the TOM channel, which imports proteins into mitochondria, in retrotranslocation of MAD substrates out of the organelle. In complementary studies, we identified a novel ER proteostasis pathway that has overlap- ping function with ERAD, but has higher throughput and contributes to the ER stress response in yeast, mam- malian cells and cellular models for a newly identified congenital muscular dystrophy (CHKB CMD). In this path- way, lipid droplets (LDs), organelles that form at ER membranes, act as escape hatches for large-scale removal of unfolded ER proteins and degradation of those proteins and their LD carriers. Here, degradation occurs by microautophagy, a conserved but understudied form of autophagy that does not rely on autophagosomes or core ATG genes for delivery of cargoes to the vacuole (yeast lysosome). Rather, LD uptake occurs by direct contact with the vacuole at invaginations of the vacuolar membrane, and LDs are released into the vacuolar lumen by membrane scission mediated by the endosomal sorting complex required for transport (ESCRT). Important fu- ture goals are to understand the mechanism of MAD function within mitochondria, and the physiological conse- quences of MAD-mediated mitochondrial proteostasis. Another important goal is to identify components and functional consequences of ER-PERM, the pathway for ER proteostasis mediated by ESCRT and microlipoph- agy, in yeast and mammalian cells. These studies will reveal mechanisms and functions of ER-PERM and targets for treatment of CHKB CMD, a life-threatening disease for which there is no cure.