Compromised Mitochondrial Protein Import Acts as a Signal for UPRmt

Abstract

Summary: The induction of the mitochondrial unfolded protein response (UPRmt) results in increased transcription of the gene encoding the mitochondrial chaperone HSP70. We systematically screened the C. elegans genome and identified 171 genes that, when knocked down, induce the expression of an hsp-6 HSP70 reporter and encode mitochondrial proteins. These genes represent many, but not all, mitochondrial processes (e.g., mitochondrial calcium homeostasis and mitophagy are not represented). Knockdown of these genes leads to reduced mitochondrial membrane potential and, hence, decreased protein import into mitochondria. In addition, it induces UPRmt in a manner that is dependent on ATFS-1 but that is not antagonized by the kinase GCN-2. We propose that compromised mitochondrial protein import signals the induction of UPRmt and that the mitochondrial targeting sequence of ATFS-1 functions as a sensor for this signal. : Unfolded protein stress is proposed to be the signal that triggers UPRmt. Rolland et al. propose instead that a decrease in mitochondrial membrane potential acts as a signal. Furthermore, they show that the MTS of the transcription factor ATFS-1 is essential to sense this signal and activate UPRmt. Keywords: C. elegans, mitochondria, UPRmt, ATFS-1, GCN-2, hsp-6, hsp-60