Abstract
Both protein quality and mitochondrial quality are vital for the cellular activity, and impaired proteostasis and mitochondrial dysfunction are common etiologies of aging and age‐related disorders. Here, we report that the mitochondrial outer membrane protein FUNDC1 interacts with the chaperone HSC70 to promote the mitochondrial translocation of unfolded cytosolic proteins for degradation by LONP1 or for formation of non‐aggresomal mitochondrion‐associated protein aggregates (MAPAs) upon proteasome inhibition in cultured human cells. Integrative approaches including csCLEM, Apex, and biochemical analysis reveal that MAPAs contain ubiquitinated cytosolic proteins, autophagy receptor p62, and mitochondrial proteins. MAPAs are segregated from mitochondria in a FIS1‐dependent manner and can subsequently be degraded via autophagy. Although the FUNDC1/HSC70 pathway promotes the degradation of unfolded cytosolic proteins, excessive accumulation of unfolded proteins on the mitochondria prior to MAPA formation impairs mitochondrial integrity and activates AMPK, leading to cellular senescence. We suggest that human mitochondria organize cellular proteostatic response at the risk of their own malfunction and cell lethality.
Synopsis
An interaction between mitochondrial outer membrane protein FUNDC1 and chaperone HSC70 promotes degradation or aggregation of unfolded cytosolic proteins on the mitochondria, thereby maintaining cellular proteostasis but reducing mitochondrial fitness.
Upon proteostatic stress, FUNDC1 interacts with HSC70 to promote the mitochondrial translocation of proteasomal clients, which are subsequently degraded by LONP1.
Mitochondrial translocation of proteasomal clients promotes the formation of mitochondrion‐associated protein aggregates (MAPAs).
MAPAs are distinct from aggresomes and contain ubiquitinated proteins, P62 and mitochondrial proteins.
FUNDC1 mediates the autophagic degradation of MAPAs, linking mitophagy and aggrephagy.
FUNDC1/HSC70‐mediated mitochondrial translocation of proteasomal clients prior to MAPA formation contributes to cell senescence.
The EMBO Journal (2019) 38: e98786
- Received December 7, 2017.
- Revision received August 25, 2018.
- Accepted October 4, 2018.
- © 2018 The Authors
Subscribers, please sign in with your username and password.
Log in using your username and password
Log in through your institution
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$35.00
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.
EMBO Members please login here to access the journals
Subscribe to the Journal
Recommend to your Librarian
