Mitochondrial Origin of Cytosolic Protein Aggregation

Abstract

One common consequence of cytosolic proteostasis stress is the formation of protein aggregates that are attached to the mitochondrial outer membrane. Although many cytosolic factors have been shown to regulate the aggregation of cytosolic proteins, it remains unknown why cytosolic protein aggregates are attached to the mitochondria. Here we show that in budding yeast, Tom70, a conserved receptor for mitochondrial import, nucleates the stress-induced aggregation of cytosolic proteins. Anchoring Tom70 or some of its substrates on the vacuole membrane converts this aggregate-free organelle into a primary site for the formation and attachment of cytosolic protein aggregates. This feature is rooted in the misfolding of some, but not all, Tom70 substrates in the cytosol. Our results suggest an unexpected mitochondrial origin of cytosolic protein aggregation.