Miro1 Protects Against Acute Kidney Injury Through Modulating Mitochondrial Homeostasis via Interaction With Sirt6.

Acute kidney injury (AKI) is highly prevalent worldwide but lacks specific treatments. Mitochondrial dysfunction plays a central role in its pathogenesis, making mitochondrial protection a promising therapeutic strategy. Miro1 is a key regulator of mitochondrial dynamics, yet its involvement in AKI remains unexplored. In this study, we found that Miro1 expression was significantly downregulated in renal tubular cells from AKI patients and in multiple murine AKI models. Functional studies demonstrated that Miro1 loss aggravated tubular cell injury and mitochondrial dysfunction, whereas Miro1 overexpression exerted protective effects. Mechanistically, we identified Sirt6 as a novel interacting partner of Miro1. Sirt6 directly deacetylated Miro1 at lysine residue K182, which inhibited its ubiquitin-proteasome degradation and maintained Miro1 protein stability. Disruption of Sirt6 activity led to enhanced Miro1 downregulation and increased tubular cell apoptosis, while Sirt6 activation reversed these detrimental effects in a deacetylase-dependent manner. Reciprocal rescue experiments further confirmed that Miro1 serves as a critical downstream effector of Sirt6. Collectively, our findings uncover the Sirt6-Miro1 axis as a previously unrecognized protective mechanism in AKI, wherein Sirt6 stabilizes Miro1 via deacetylation to preserve mitochondrial homeostasis and alleviate kidney injury. This axis may represent a novel therapeutic target for AKI intervention.