STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism

• Published in: Nature communications Vol. 10; no. 1; pp. 2059 - 17
• Main Authors: Xian, Hongxu, Yang, Qiaoyun, Xiao, Lin, Shen, Han-Ming, Liou, Yih-Cherng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.05.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/109; 13/31; 13/89; 14; 14/19; 14/28; 14/34; 14/35; 631/80/313/2104; 631/80/39/2348; 631/80/642/333; Autophagy; Depletion; Electron transport; Endoplasmic Reticulum - metabolism; Gene Knockout Techniques; HEK293 Cells; HeLa Cells; Homeostasis; Humanities and Social Sciences; Humans; Membrane proteins; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membranes; Mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mitophagy; multidisciplinary; Oligomerization; Parkin protein; Phagocytosis; Proteins; Proteomics; PTEN-induced putative kinase; Qa-SNARE Proteins - metabolism; Quality control; Science; SNAP receptors; Syntaxin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10096-1

Mitophagy is the selective autophagic targeting and removal of dysfunctional mitochondria. While PINK1/Parkin-dependent mitophagy is well-characterized, PINK1/Parkin-independent route is poorly understood. Using structure illumination microscopy (SR-SIM), we demonstrate that the SNARE protein Syntaxin 17 (STX17) initiates mitophagy upon depletion of outer mitochondrial membrane protein Fis1. With proteomics analysis, we identify the STX17-Fis1 interaction, which controls the dynamic shuffling of STX17 between ER and mitochondria. Fis1 loss results in aberrant STX17 accumulation on mitochondria, which exposes the N terminus and promotes self-oligomerization to trigger mitophagy. Mitochondrial STX17 interacts with ATG14 and recruits core autophagy proteins to form mitophagosome, followed by Rab7-dependent mitophagosome-lysosome fusion. Furthermore, Fis1 loss impairs mitochondrial respiration and potentially sensitizes cells to mitochondrial clearance, which is mediated through canonical autophagy machinery, closely linking non-selective macroautophagy to mitochondrial turnover. Our findings uncover a PINK1/Parkin-independent mitophagic mechanism in which outer mitochondrial membrane protein Fis1 regulates mitochondrial quality control. Mitophagy plays a critical role in cellular homeostasis, and PINK1/Parkin-mediated mitophagy is the most thoroughly characterized. Here, Xian et al. show that STX17 induces mitophagy via a macroautophagy pathway regulated by Fis1, by a PINK1/Parkin-independent route.