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

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.

Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture

“…This was consistent with the degradation of Miro by this pathway (Liu et al, 2012; Wang et al, 2011); the consequent arrest of mitochondrial movement made it unlikely that this process required damaged mitochondria to be translocated to the soma. That said, the observation of local mitophagy does not exclude the possibility that, under some circumstances (Lin et al, 2017) and particularly those where there is unlikely to be enough ATP to support the PINK1/Parkin pathway, older or slightly damaged mitochondria will not be arrested and will preferentially move retrograde.…”

“…Most recently, a study employed exposures of dorsal root ganglion neurons for 6 hours or longer to very low levels of antimycin A to mimic a long-term mild stress, followed by an hour of recovery. In those conditions, membrane potential and directionality correlated, with better membrane potentials preferentially moving anterograde (Lin et al, 2017). One further complication need be mentioned: if retrogradely moving mitochondria are destined for degradation, once they enter the soma they should be kept apart for mitophagy.…”

Mitochondrial-cytoskeletal interactions: dynamic associations that facilitate network function and remodeling

“…A novel mechanism linking syntaphilin to the removal of stressed mitochondria has recently been described, in which the application of the respiratory complex III inhibitor Antimycin A1 to primary neurons induces the budding of syntaphilin-positive carrier vesicles from the ends of damaged mitochondria along axons. These vesicles are then transported in association with late endosomes toward the soma for lysosomal degradation [22]. The increased prevalence of syntaphilin-positive vesicles in neurons from neurodegenerative disease models suggests that the formation of these vesicles may be a response to chronic stress, but the mechanism leading to their generation remains to be determined, as it is independent of both Parkin and Drp1 activity [22].…”

“…These vesicles are then transported in association with late endosomes toward the soma for lysosomal degradation [22]. The increased prevalence of syntaphilin-positive vesicles in neurons from neurodegenerative disease models suggests that the formation of these vesicles may be a response to chronic stress, but the mechanism leading to their generation remains to be determined, as it is independent of both Parkin and Drp1 activity [22]. …”

Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane

“…One of the essential components of normal mitochondrial dynamics is the ability to move along axons delivering energy to the distal sites, synapses, and axonal growth cone (Sheng and Cai, 2012). Axonal trafficking is also essential for delivering damaged mitochondria to the soma for degradation (Lin et al, 2017). Mounting data generated in tissue and cells from AD patients and in animal models of FAD suggest mitochondrial axonal trafficking is affected early in the disease prior to the onset of memory impairment or the development of amyloid plaques (Correia et al, 2016; Galindo et al, 2010; Pigino et al, 2003; Selfridge et al, 2013; Tillement et al, 2011; Trushina et al, 2012; Yao et al, 2009; Ye et al, 2012).…”