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
Related in: MedlinePlus
License 1 - License 2
Mentions: It has been reported that damaged mitochondria move retrograde toward the soma, presumably, to undergo mitophagy there (Miller and Sheetz, 2004; Cai et al., 2012). However, our observations of mitochondrial motility arrest (Wang et al., 2011) and the accumulation of aged mitochondrial proteins in distal processes (Ferree et al., 2013) argue against this model. In addition, a recent study has shown autophagosome formation in distal regions of undamaged neurons in culture (Maday et al., 2012). To determine whether damaged mitochondria in distal axons could locally recruit autophagosomes, we expressed the autophagosome marker GFP-LC3 along with mt-KR in hippocampal neurons. GFP-LC3 is a cytosolic protein, but upon induction of autophagy, it gets lipidated and incorporated into autophagosomes forming distinct puncta (Mizushima and Komatsu, 2011). Mitochondrially targeted BFP (mt-BFP) was also expressed to mark mitochondria. After activation of mt-KR, we observed GFP-LC3 accumulation on mitochondria, indicating the formation of mitochondrion-containing autophagosomes (Fig. 3, A and B). In some instances, the autophagosomal mitochondrion eventually disappeared, presumably, as a result of the formation of autolysosomes. Our findings establish that the initial stages of mitophagy, specifically colocalization with LC3-positive autophagosomes, can occur locally in axons.
Affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138 F.M. Kirby Neurobiology Center, Children's Hospital Boston, Boston, MA 02115.