Rhes, a Striatal-Enriched Protein, Promotes Mitophagy Via Nix.
Elimination of dysfunctional mitochondria via mitophagy is essential for cell survival and neuronal functions. But, how impaired mitophagy participates in tissue-specific vulnerability in the brain remains unclear. Here we discovered that Rhes, a striatal-enriched protein, is a major regulator of mitophagy in the striatum. Rhes predominantly interact with dysfunctional mitochondria and degrades them via mitophagy, and this function is exacerbated by the striatal toxin, 3-nitropropionic acid (3-NP). 3-NP induces mitochondrial swelling, loss of cristae and neuronal cell death only in WT but not Rhes KO striatum. Mechanistically, Rhes disrupts the mitochondrial membrane potential ({Delta}{Psi}m) and interacts with mitophagy receptor, Nix. In Nix KO cells, Rhes fails to disrupt {Delta}{Psi}m or eliminate dysfunctional mitochondria. Moreover, Rhes travels to the neighboring cell and associates with dysfunctional mitochondria via Nix. Collectively, Rhes is a major regulator of mitophagy via Nix which may determine striatal vulnerability in the brain.