A mitochondrial FUNDC1/HSC70 interaction organizes the proteostatic stress response at the risk of cell morbidity.
EMBO Journal; Feb2019, Vol. 38 Issue 3, p1-20, 20p, 9 Graphs
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. 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. [ABSTRACT FROM AUTHOR]
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