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: The recruitment of expressed Parkin to axonal mitochondria raised the question of whether endogenous Parkin was required for damage-induced mitophagy. We therefore compared mitophagy in hippocampal axons of Parkin+/+ and Parkin−/− mice (Goldberg et al., 2003). In microfluidic chambers, GFP-LC3 was coexpressed with mt-DsRed to monitor autophagosome formation. In Parkin+/+ axons, the fraction of mitochondria colocalizing with GFP-LC3–positive autophagosomes increased from 4% before to 33% after 35 min of Antimycin A treatment in the perfusion chamber (P < 0.05; Fig. 7, A, B, and E). In contrast, in Parkin−/− axons, Antimycin A did not increase mitochondrial colocalization with autophagosomes (P = 1; Fig. 7, C–E). Damage-induced mitophagy could be rescued in Parkin−/− axons by expressing mCherry-Parkin (Fig. S4 A). Thus, depolarization-induced initiation of mitophagy in neuronal axons both triggers Parkin recruitment and requires Parkin. We also examined damage-induced mitochondrial fragmentation and found that treatment with Antimycin A for 20 min caused a significant decrease in mitochondrial size in both Parkin+/+ and Parkin−/− axons (P < 0.01; Fig. 7 F). We conclude that Parkin is not required for the remodeling of depolarized mitochondria, only for the subsequent recruitment of the autophagosome.
Affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138 F.M. Kirby Neurobiology Center, Children's Hospital Boston, Boston, MA 02115.