Abstract
The failure to trigger mitophagy is implicated in the pathogenesis of familial Parkinson disease that is caused by PINK1 or Parkin mutations. According to the prevailing PINK1-Parkin signaling model, mitophagy is promoted by the mitochondrial translocation of Parkin, an essential PINK1-dependent step that occurs via a previously unknown mechanism. Here we determined that critical concentrations of NO was sufficient to induce the mitochondrial translocation of Parkin even in PINK1 deficiency, with apparent increased interaction of full-length PINK1 accumulated during mitophagy, with neuronal nitric oxide synthase (nNOS). Specifically, optimum levels of NO enabled PINK1-null dopaminergic neuronal cells to regain the mitochondrial translocation of Parkin, which appeared to be significantly suppressed by nNOS-null mutation. Moreover, nNOS-null mutation resulted in the same mitochondrial electron transport chain (ETC) enzyme deficits as PINK1-null mutation. The involvement of mitochondrial nNOS activation in mitophagy was further confirmed by the greatly increased interactions of full-length PINK1 with nNOS, accompanied by mitochondrial accumulation of phospho-nNOS (Ser(1412)) during mitophagy. Of great interest is that the L347P PINK1 mutant failed to bind to nNOS. The loss of nNOS phosphorylation and Parkin accumulation on PINK1-deficient mitochondria could be reversed in a PINK1-dependent manner. Finally, non-toxic levels of NO treatment aided in the recovery of PINK1-null dopaminergic neuronal cells from mitochondrial ETC enzyme deficits. In summary, we demonstrated the full-length PINK1-dependent recruitment of nNOS, its activation in the induction of Parkin translocation, and the feasibility of NO-based pharmacotherapy for defective mitophagy and ETC enzyme deficits in Parkinson disease.
Highlights
A novel mechanism underlying mitochondrial translocation of Parkin during mitophagy is uncovered
NO-induced Mitochondrial Translocation of Parkin—In our previous study [33], dysregulated NO signaling was implicated in PINK1 deficiency-related electron transport chain (ETC) enzyme deficits, including complex IV deficits, that were significantly restored by NO
We identified a novel mechanism underlying the mitochondrial recruitment of Parkin by PINK1 during CCCP-induced mitophagy
Summary
A novel mechanism underlying mitochondrial translocation of Parkin during mitophagy is uncovered. We demonstrated the full-length PINK1-dependent recruitment of nNOS, its activation in the induction of Parkin translocation, and the feasibility of NO-based pharmacotherapy for defective mitophagy and ETC enzyme deficits in Parkinson disease. We have demonstrated previously that PINK1 deficiency results in a mitochondrial complex IV deficit because of reduced expression of the complex IV assembly factor leucinerich pentatricopeptide repeat containing (LRPPRC) and dysregulated NO signaling [33] and that low levels of NO treatment help PINK1-deficient dopaminergic neurons restore the function of their defective PINK1-LRPPRC-Hsp60-complex IV signaling axis [33] It remains unclear how the functional loss of PINK1 leads to a disturbance in NO signaling and how dysregulated NO signaling affects various mitochondrial functions. We showed that increased interaction of full-length PINK1 with nNOS and its activation are involved in induction of Parkin translocation and mitophagy and that precise levels of NO allow PINK1-null dopaminergic neuronal cells to recover from defective mitophagy and ETC enzyme deficits. Our findings demonstrate that mitochondrial dysfunction in PINK1-deficient dopaminergic cells can be rescued significantly upon NO treatment, at least in part because of the restoration of Parkin translocation and mitophagy
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