Compartmentalized Regulation of Parkin-Mediated Mitochondrial Quality Control in the Drosophila Nervous System In Vivo

Abstract

In neurons, the normal distribution and selective removal of mitochondria are considered essential for maintaining the functions of the large asymmetric cell and its diverse compartments. Parkin, a E3 ubiquitin ligase associated with familial Parkinson's disease, has been implicated in mitochondrial dynamics and removal in cells including neurons. However, it is not clear how Parkin functions in mitochondrial turnover in vivo, or whether Parkin-dependent events of the mitochondrial life cycle occur in all neuronal compartments. Here, using the live Drosophila nervous system, we investigated the involvement of Parkin in mitochondrial dynamics, distribution, morphology, and removal. Contrary to our expectations, we found that Parkin-deficient animals do not accumulate senescent mitochondria in their motor axons or neuromuscular junctions; instead, they contain far fewer axonal mitochondria, and these displayed normal motility behavior, morphology, and metabolic state. However, the loss of Parkin did produce abnormal tubular and reticular mitochondria restricted to the motor cell bodies. In addition, in contrast to drug-treated, immortalized cells in vitro, mature motor neurons rarely displayed Parkin-dependent mitophagy. These data indicate that the cell body is the focus of Parkin-dependent mitochondrial quality control in neurons, and argue that a selection process allows only healthy mitochondria to pass from cell bodies to axons, perhaps to limit the impact of mitochondrial dysfunction.

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

“…These results suggest that neurons may utilize a specialized mechanism for mitochondrial quality control through selective bi-directional transport, thus removing stressed mitochondria from and replenishing healthy ones to distal axons. Our findings are recapitulated in the intact in vivo nervous system where mitochondrial turnover is mainly found to the soma (Devireddy et al, 2015; Sung et al, 2016). Impaired mitochondrial transport associated with major neurodegenerative diseases likely contributes to the long-term accumulative effects that lead to mitochondrial pathology in distal axons.…”

“…It also remains unclear whether other mechanisms play an early role in the maintenance of axonal mitochondrial quality before the activation of Parkin-mediated mitophagy. Recent studies with genetic PINK1 and Parkin mutations support the model that mitochondrial turnover is mainly restricted to the soma in the Drosophila nervous system in vivo (Devireddy et al, 2015; Sung et al, 2016), thus calling for investigations into how damaged mitochondria are removed from axons under pathophysiological conditions.…”

Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture

“…Experimental conditions that poison all the mitochondria in a neuron will therefore also likely shut down the PINK1/Parkin pathway to mitophagy (Cai et al, 2012; Van Laar et al, 2011). There are additional routes to mitophagy that are not dependent on either PINK1 or Parkin or both (Roberts et al, 2016), and the relative contribution and extent of redundancy of these alternatives is not clear (Devireddy et al, 2015; Sung et al, 2016). Nor are the actions of PINK1 and Parkin necessarily restricted to triggering mitophagy (Johnson et al, 2012; Morais et al, 2014; Muller-Rischart et al, 2013); in particular, as mentioned above, they can also mediate formation of MDVs and it is not known what determines the choice between MDV formation and full-fledged mitophagy.…”

Autophagy core machinery: overcoming spatial barriers in neurons

“…Furthermore, in both cases, abnormal mitochondrial morphology is only observed in the cell body but not in axons. These results suggest that neurons handle mitochondrial quality control through PARK2-PINK1-dependent mitophagy in a compartment-specific manner [89, 90]. Such compartmentalization of neuronal autophagy is further demonstrated by a recent inquiry into the dynamics of bulk autophagy, following the formation and maturation of autophagosomes within various regions of the neuron.…”

“…Although the axonal transport of mitochondria is impaired in the absence of PINK1, mitochondrial density in both the axon and soma remains relatively unchanged [89]. Conversely, in PARK2-deficient cells, reduced mitochondrial flux along axons mainly stems from a decrease in the number of axonally located mitochondria and not diminished transport [90]. Furthermore, in both cases, abnormal mitochondrial morphology is only observed in the cell body but not in axons.…”