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

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. [Display omitted] •Pathophysiological stress induces the removal of defective mitochondria from axons•Stressed mitochondria release SNPH cargos to enhance their retrograde transport•SNPH cargos undergo retrograde transport en route late endosomes to lysosomes•SNPH-mediated response is activated in the early disease stages of ALS and AD Lin and Cheng et al. reveal a new mechanism maintaining axonal mitochondrial integrity by releasing anchoring protein syntaphilin from stressed mitochondria, thus facilitating the removal of dysfunctional mitochondria from axons before activation of Parkin-mediated mitophagy under physiological and pathological conditions.