Rhes, a striatal-enriched protein, promotes mitophagy via Nix

Abstract

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 find that striatal-enriched protein, Rhes, is a critical regulator of mitophagy and striatal vulnerability in brain. In vivo interactome and density fractionation reveal that Rhes coimmunoprecipitates and cosediments with mitochondrial and lysosomal proteins. Live-cell imaging of cultured striatal neuronal cell line shows Rhes surrounds globular mitochondria, recruits lysosomes, and ultimately degrades mitochondria. In the presence of 3-nitropropionic acid (3-NP), an inhibitor of succinate dehydrogenase, Rhes disrupts mitochondrial membrane potential (ΔΨm) and promotes excessive mitophagy and cell death. Ultrastructural analysis reveals that systemic injection of 3-NP in mice promotes globular mitochondria, accumulation of mitophagosomes, and striatal lesion only in the wild-type (WT), but not in the Rhes knockout (KO), striatum, suggesting that Rhes is critical for mitophagy and neuronal death in vivo. Mechanistically, Rhes requires Nix (BNIP3L), a known receptor of mitophagy, to disrupt ΔΨm and promote mitophagy and cell death. Rhes interacts with Nix via SUMO E3-ligase domain, and Nix depletion totally abrogates Rhes-mediated mitophagy and cell death in the cultured striatal neuronal cell line. Finally, we find that Rhes, which travels from cell to cell via tunneling nanotube (TNT)-like cellular protrusions, interacts with dysfunctional mitochondria in the neighboring cell in a Nix-dependent manner. Collectively, Rhes is a major regulator of mitophagy via Nix, which may determine striatal vulnerability in the brain.

Rhes Tunnels: A Radical New Way of Communication in the Brain's Striatum?

“…In our preliminary findings, we found that Rhes, which promotes mitophagy, can travel via TNT‐like Rhes tunnel to neighboring striatal neuronal cells and interact with damaged mitochondria there. [ 104 ] Thus, TNT‐like Rhes tunnels may be used for the purpose of mitochondrial surveillance. Striatum also consists of two distinct anatomical regions—matrix and striosomes—that are distinguished based on the different neurochemical markers.…”

Exaggerated mitophagy: a weapon of striatal destruction in the brain?

“…Our study demonstrates that Rhes requires the mitophagy receptor NIX to clear damaged mitochondria [73]. In cells that lack the NIX receptor, the Rhes protein fails to induce mitophagy.…”

“…We found that Rhes is a potent inducer of cellular protrusion (Rhes tunnel) and transports endosomes and lysosomes, but not mitochondria, to the neighboring cells; however, we found that Rhes specially associates with the damaged mitochondria in the neighboring cells via NIX [73,85]. This indicates that Rhes has the capacity of intercellular mitochondrial surveillance in vitro.…”

“…We have now found that Rhes selectively interacts with damaged mitochondria and removes them via mitophagy, wherein the damaged mitochondria are degraded via lysosomes [73]. Normally, the Rhes protein does not interact with elongated or 'healthy-looking' mitochondria, but it appears to surround the globular or 'unhealthy' mitochondria.…”

“…3-NP-induced glutamate excitotoxicity may further worsen Rhes-induced mitophagy. Excitotoxicity can also occur in the cortex [53,73]; however, 3-NP does not elicit lesions in the cortex. Parkin, a ubiquitous mitophagy regulator, was shown to mediate NMDA receptor excitotoxicity-induced mitophagy in cortical neurons [74].…”