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: We then asked whether PINK1 is similarly required for autophagosome formation on damaged mitochondria. In PINK1+/+ axons, 40 µM Antimycin A increased the fraction of mitochondria colocalizing with GFP-LC3 autophagosomes from 3 to 18% (P < 0.01; Fig. 9, A, B, and E). In PINK1−/− axons, however, there was a smaller Antimycin A–induced change in the fractions of mitochondria colocalizing with autophagosomes (from 3 to 8%), and that change did not reach statistical significance (P = 0.09; Fig. 9, C–E). This represented significantly less recruitment of GFP-LC3 autophagosomes in PINK1−/− axons compared with PINK1+/+ axons (P < 0.05). Expression of exogenous PINK1-FLAG rescued autophagosome formation on mitochondria in PINK1−/− axons. The fraction of GFP-LC3–positive mitochondria increased from 6 to 16% after Antimycin A treatment (P < 0.05; Fig. 9 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.