The mitophagy receptor Nix coordinates nuclear calcium signaling to modulate the muscle phenotype

Abstract

SummaryMitochondrial quality control is critical in muscle to ensure both contractile and metabolic function. Nix is a BCL-2 family member, mitophagy receptor, and has recently been implicated in muscle atrophy. Human GWAS suggests altered Nix expression could predispose individuals to manifestations of mitochondrial disease. To interrogate the role of Nix in skeletal muscle, we generated a muscle-specific knockout model. Nix knockout mice displayed a ragged-red fibre phenotype, along with accumulation of senescent mitochondria and sarcoplasmic reticulum. Intriguingly, Nix knockout mice were more insulin sensitive with a corresponding increase in glycogen-rich muscle fibres. Kinome- and gene expression analyses revealed that Nix knockout impairs NFAT and canonical myostatin signaling, with alterations in muscle fibre-type composition and evidence of regeneration. Experiments in myotubes demonstrated that Nix modulates mitophagy, and also ER-phagy through a distinct mechanism leading to nuclear calcium signaling. Collectively, these observations indicate that Nix maintains muscle integrity and an oxidative phenotype.HighlightsRemoval of Nix in muscle results in a compensated mitochondrial myopathyNix knockout alters cell signaling and oxidative muscle gene expressionNix also modulates myostatin expression and Smad signalingNix knockout alters muscle fibre-type distribution and muscle functionSignificanceHow mitochondria respond to cell stress to activate cell signaling pathways remains poorly understood. We show that genetic removal of the mitophagy receptor Nix from muscle leads to alterations in cell signaling and the muscle phenotype. These observations help explain how selective autophagy pathways can modulate tissue homeostasis during metabolic stress.