LONP1 and mtHSP70 cooperate to promote mitochondrial protein folding

ABSTRACT: Because 99% of the mitochondrial proteome is encoded by the nucleus, most mitochondrial precursor polypeptides are imported from the cytosol into the mitochondrion, where they must efficiently fold into their functional state. Mitochondrial precursors are imported as unfolded polypeptides due to the limited pore size of the import machinery. For proteins of the mitochondrial matrix and inner membrane, two separate and highly conserved chaperone systems, HSP60 and mitochondrial HSP70 (mtHSP70), facilitate protein folding. Here we show that LONP1, a AAA+ protease of the mitochondrial matrix, works with the mtHSP70 chaperone system to promote mitochondrial protein folding. Inhibition of LONP1 results in aggregation of a protein subset similar to that caused by knockdown of DNAJA3, a co-chaperone of mtHSP70. LONP1 is required for DNAJA3 and mtHSP70 solubility, and its ATPase, but not its protease activity, is required for this function. In vitro, LONP1 collaborates with mtHSP70 and its co-factors to stabilize a folding intermediate of OXA1L. In the absence of LONP1, the interaction of mtHSP70 with OXA1L is futile and results in substrate-induced coaggregation. Our results identify mitochondrial LONP1 as a critical factor in the mtHSP70 folding pathway and directly demonstrate its long suspected chaperone activity.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Brett Lomenick  

LAB HEAD: Spiros D. Garbis

PROVIDER: PXD021939 | Pride | 2020-12-07

REPOSITORIES: Pride