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Mitochondrial protein import stress regulates the LC3 lipidation step of mitophagy through NLRX1 and RRBP1

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2022

Mol Cell. 2022 Jun 16;S1097-2765(22)00540-8. doi: 10.1016/j.molcel.2022.06.004. Online ahead of print.

Mitochondrial protein import stress regulates the LC3 lipidation step of mitophagy through NLRX1 and RRBP1

Samuel A Killackey, Yuntian Bi, Fraser Soares, Ikram Hammi, Nathaniel J Winsor, Ali A Abdul-Sater, Dana J Philpott, Damien Arnoult, Stephen E Girardin

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada. Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada. INSERM U1197, Hôpital Paul Brousse, Bâtiment Lavoisier, 94807 Villejuif Cedex, France. Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. School of Kinesiology and Health Science, Muscle Health Research Centre (MHRC), Faculty of Health, York University, Toronto, ON M3J 1P3, Canada.

Service type: Knockout mice

Abstract

Protein import into mitochondria is a highly regulated process, yet how cells clear mitochondria undergoing dysfunctional protein import remains poorly characterized. Here we showed that mitochondrial protein import stress (MPIS) triggers localized LC3 lipidation. This arm of the mitophagy pathway occurs through the Nod-like receptor (NLR) protein NLRX1 while, surprisingly, without the engagement of the canonical mitophagy protein PINK1. Mitochondrial depolarization, which itself induces MPIS, also required NLRX1 for LC3 lipidation. While normally targeted to the mitochondrial matrix, cytosol-retained NLRX1 recruited RRBP1, a ribosome-binding transmembrane protein of the endoplasmic reticulum, which relocated to the mitochondrial vicinity during MPIS, and the NLRX1/RRBP1 complex in turn controlled the recruitment and lipidation of LC3. Furthermore, NLRX1 controlled skeletal muscle mitophagy in vivo and regulated endurance capacity during exercise. Thus, localization and lipidation of LC3 at the site of mitophagosome formation is a regulated step of mitophagy controlled by NLRX1/RRBP1 in response to MPIS.

Keywords: NLRX1; Nod-like receptors; mitochondria; mitochondrial protein import; mitophagy.

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