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

Neuron | May 3, 2017

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.

Pubmed ID: 28472658 RIS Download

Mesh terms: Aged | Aged, 80 and over | Alzheimer Disease | Amyotrophic Lateral Sclerosis | Animals | Axons | Calcium | Carrier Proteins | Cerebral Cortex | Endosomes | Female | Humans | Male | Mice | Mice, Knockout | Microscopy, Immunoelectron | Microtubule-Associated Proteins | Middle Aged | Mitochondria | Mitochondrial Degradation | Motor Neurons | Mutation | Nerve Tissue Proteins | Neurons | Rats | Spinal Cord | Stress, Physiological | Ubiquitin-Protein Ligases | Vesicular Transport Proteins

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Associated grants

  • Agency: Intramural NIH HHS, Id: ZIA NS003029-10
  • Agency: NIA NIH HHS, Id: R00 AG033658
  • Agency: NINDS NIH HHS, Id: ZIA NS003029
  • Agency: Intramural NIH HHS, Id: ZIA NS002946-20
  • Agency: NINDS NIH HHS, Id: ZIA NS002946
  • Agency: NINDS NIH HHS, Id: R01 NS089737
  • Agency: Intramural NIH HHS, Id: Z01 NS002946-12

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