Mitochondria-ER cooperation: NLRX1 detects mitochondrial protein import stress and promotes mitophagy through the ER protein RRBP1

ABSTRACTMitochondria rely on efficient protein import across their membranes for optimal function. We have shown that numerous mitochondrial stressors all converge on a common pathway disrupting this import efficiency. We identified a novel pathway involving NLRX1 and RRBP1 that responds to this import stress, resulting in LC3 lipidation, mitochondrial targeting and ultimate degradation. Furthermore, we demonstrated the relevance of this mitophagy axis in murine skeletal muscle following acute exercise. We propose that mitochondrial protein import stress is an underlying, common trigger for mitophagy, offering a novel avenue for therapeutic exploration and mechanistic insight.KEYWORDS: AutophagyexerciseimportmitochondriamitophagyNLRproteostasis AcknowledgmentThis work was supported by the Canadian Institutes of Health Research operating grant 000303157 (S.E.G.). S.A.K. is supported by the CIHR Vanier Canada Graduate Scholarship.Disclosure statementNo potential conflict of interest was reported by the author(s).Additional informationFundingThe work was supported by the Canadian Institutes of Health Research [000303157]