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.
Highlights
Mitophagy is the selective autophagic targeting and removal of dysfunctional mitochondria
Syntaxin 17 (STX17) was found to interact with Fis[1], but not with other proteins involved in mitochondrial dynamics, including mitochondrial fission factor (Mff), Drp[1], Mfn[1], Mfn[2], and OPA1, suggesting a selective association between Fis[1] and STX17 (Fig. 1d)
We examined the localization of mCherry-tagged Fis[1] and green fluorescent protein (GFP)-tagged STX17 by immunofluorescence analysis in HeLa cells, due to the incapability of commercial antibody to analyze endogenous STX17 (Fig. 1e and Supplementary Fig. 1c)
Summary
Mitophagy is the selective autophagic targeting and removal of dysfunctional mitochondria. PINK1/Parkin-independent pathways of mitochondrial elimination involving mitophagy receptors, including Nix (BNIP3L, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like), FUNDC1 (FUN14 domain-containing protein 1), Bcl-2-L-13 (Bcl-2-like protein 13), and FKBP8 (peptidyl-prolyl cis–trans isomerase FKBP8) have been reported[14,25,26,27,28,29,30]. It remains unclear whether additional mechanisms of PINK1/ Parkin-independent mitophagy could exist in fetal tissues or cell lines, which show no or low endogenous Parkin expression[31,32]. The bona fide role of mitochondrial Fis[1] remains unknown
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