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STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism

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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
    National University of Singapore)

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.

Suggested Citation

  • Hongxu Xian & Qiaoyun Yang & Lin Xiao & Han-Ming Shen & Yih-Cherng Liou, 2019. "STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10096-1
    DOI: 10.1038/s41467-019-10096-1
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