Releasing Syntaphilin Removes Stressed Mitochondria from Axons Independent of Mitophagy under Pathophysiological Conditions

Mei Yao Lin, Xiu Tang Cheng, Prasad Tammineni, Yuxiang Xie, Bing Zhou, Qian Cai, Zu Hang Sheng

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Chronic mitochondrial stress is a central problem associated with neurodegenerative diseases. Early removal of defective mitochondria from axons constitutes a critical step of mitochondrial quality control. Here we investigate axonal mitochondrial response to mild stress in wild-type neurons and chronic mitochondrial defects in Amytrophic Lateral Sclerosis (ALS)- and Alzheimer's disease (AD)-linked neurons. We show that stressed mitochondria are removed from axons triggered by the bulk release of mitochondrial anchoring protein syntaphilin via a new class of mitochondria-derived cargos independent of Parkin, Drp1, and autophagy. Immuno-electron microscopy and super-resolution imaging show the budding of syntaphilin cargos, which then share a ride on late endosomes for transport toward the soma. Releasing syntaphilin is also activated in the early pathological stages of ALS- and AD-linked mutant neurons. Our study provides new mechanistic insights into the maintenance of axonal mitochondrial quality through SNPH-mediated coordination of mitochondrial stress and motility before activation of Parkin-mediated mitophagy. Video Abstract [Figure presented]

Original languageEnglish (US)
Pages (from-to)595-610.e6
JournalNeuron
Volume94
Issue number3
DOIs
StatePublished - May 3 2017

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • AD
  • ALS
  • Mitochondrial quality control
  • axonal mitochondria
  • late endosome
  • mitochondrial transport
  • physiological stress
  • syntaphilin

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