Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin.
Bottom Line: In PINK1(-/-) axons, damaged mitochondria did not accumulate Parkin and failed to be engulfed in autophagosomes.Similarly, initiation of mitophagy was blocked in Parkin(-/-) axons.Local mitophagy likely provides rapid neuroprotection against oxidative stress without a requirement for retrograde transport to the soma.
Affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138 F.M. Kirby Neurobiology Center, Children's Hospital Boston, Boston, MA 02115.Show MeSH
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Mentions: Genetic studies have indicated that PINK1 acts upstream of Parkin in the regulation of mitochondrial integrity (Clark et al., 2006; Park et al., 2006), and stabilization of PINK1 on the outer mitochondrial membrane is essential for Parkin recruitment in nonneuronal cells (Geisler et al., 2010; Narendra et al., 2010) and cell bodies of induced pluripotent stem cell–derived neurons (Seibler et al., 2011). Similarly, PINK1 is required for basal turnover of mitochondrial respiratory chain subunits in Drosophila melanogaster (Vincow et al., 2013). However, in the cell types examined so far, PINK1 undergoes continuous synthesis and rapid degradation in the absence of mitochondrial depolarization (Narendra et al., 2010). Because axonal transport can require days or weeks, it was uncertain whether this mechanism could pertain to distal axons. We therefore examined whether PINK1 is required for recruitment of Parkin and autophagosome membranes to axonal mitochondria. Axons of hippocampal neurons from PINK1+/+ and PINK1−/− rats were treated with 40 µM Antimycin A in the perfusion chamber. In PINK1+/+ axons, the percentage of YFP-Parkin–positive mitochondria increased from 16 to 48% after 20 min (P < 0.05; Fig. 8, A, B, and E). In contrast, YFP-Parkin failed to accumulate on Antimycin A–treated mitochondria of PINK1−/− axons (9% before and 12% after; P = 0.5; Fig. 8, C–E).
Affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138 F.M. Kirby Neurobiology Center, Children's Hospital Boston, Boston, MA 02115.