摘要

Mitophagy eliminates excess and damaged mitochondria via autophagy, yet its regulatory mechanisms and physiological roles remain incompletely defined. Here, we show that the mitophagy receptors BNIP3 and NIX govern basal mitophagy in mouse tissues. Bnip3-/-Nix-/- mice accumulate functional mitochondria across somatic tissues, exhibiting hypermetabolism and resistance to diet-induced obesity and fatty liver disease. GalNAc-siRNA-mediated knockdown of BNIP3 and NIX in liver alleviates hepatic steatosis and fibrosis in MASH mouse models. We further show that BNIP3/NIX-dependent basal mitophagy is actively surveilled and maintained at physiological levels in somatic cells. We identified a PPTC7-FBXL4 surveillance axis, wherein PPTC7 recognizes BNIP3/NIX and targets them for FBXL4-mediated ubiquitination and degradation. FBXL4 mutations cause MTDPS13 (mtDNA depletion syndrome 13), a fatal degenerative disorder characterized by severe mitochondrial loss. Strikingly, Bnip3 or Nix deletion rescues viability of the Fbxl4-/- mice. Collectively, these findings establish BNIP3/NIX-mediated mitophagy as a key determinant of mitochondrial quantity and cellular physiology.

个人简介

蒋辉博士，北京生命科学研究所/清华大学生物医学交叉研究院，高级研究员。蒋辉博士团队致力于研究线粒体质量控制及稳态调控机制，为代谢及退行性疾病开发线粒体靶点。近5年来相关工作以通讯作者发表在Cell Metabolism、Molecular Cell、EMBO Journal、Cell Reports等杂志。