LONP1 Is Required for Maturation of a Subset of Mitochondrial Proteins, and Its Loss Elicits an Integrated Stress Response

Abstract

LONP1, a AAA+ mitochondrial protease, is implicated in protein quality control, but its substrates and precise role in this process remain poorly understood. Here we have investigated the role of human LONP1 in mitochondrial gene expression and proteostasis. Depletion of LONP1 resulted in partial loss of mtDNA, complete suppression of mitochondrial translation, a marked increase in the levels of a distinct subset of mitochondrial matrix proteins (SSBP1, MTERFD3, FASTKD2 and CLPX), and the accumulation of their unprocessed forms, with intact mitochondrial targeting sequences, in an insoluble protein fraction. Depletion of LONP1 produced massive matrix protein aggregates and activated the Integrated Stress Response (ISR) pathway. These results demonstrate that LONP1 is required for maturation of a subset of its client proteins and for maintenance of mitochondrial gene expression.