STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism

Hongxu Xian, Qiaoyun Yang, Lin Xiao, Han-Ming Shen and Yih-Cherng Liou ()
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Hongxu Xian: National University of Singapore
Qiaoyun Yang: National University of Singapore
Lin Xiao: National University of Singapore
Han-Ming Shen: National University of Singapore
Yih-Cherng Liou: National University of Singapore

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10096-1

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