Compromised Mitochondrial Protein Import Acts as a Signal for UPR mt

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 172 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. For example, mitochondrial calcium homeostasis and mitophagy are not represented. When compromised, the mitochondrial processes that are represented induce UPRmt in a manner that is dependent on the transcription factor ATFS-1, but not the kinase GCN-2. Furthermore, directly or indirectly, these processes are required for the maintenance of mitochondrial membrane potential and, hence, for robust protein import into mitochondria. We propose that compromised mitochondrial protein import acts as a signal for the induction of UPRmt and present evidence that the mitochondrial targeting sequence of ATFS-1 functions as a sensor for this signal.