Klotho‐Derived Peptide 1 Protects against Acute Kidney Injury by Directly Targeting Mitochondrial ATAD3A

Acute kidney injury (AKI) is a clinical syndrome associated with severe morbidity and high mortality, for which there are no currently effective therapies. Aging, a state associated with Klotho protein decline, is an independent risk factor for AKI development and progression. Here, we report that Klotho-derived peptide 1 (KP1), a small peptide that recapitulates the renoprotective potential of Klotho, effectively protects against AKI in mouse models induced by either cisplatin or ischemia-reperfusion injury. KP1 treatment improved kidney function, ameliorated structural damage, inhibited tubular cell apoptosis, and preserved mitochondrial integrity in both models. Mechanistically, KP1 entered kidney proximal tubular epithelial cells via endocytosis, directly targeted the mitochondrial protein ATPase family AAA domain-containing protein 3A (ATAD3A), and prevented its degradation, and preserved its function. By interacting with the hypoxia inducible gene 1 (HIG1) domain family member 2A (HIGD2A) and maintaining its expression and function within the mitochondria, ATAD3A prevented cytochrome c release and inhibited caspase activation following injury, thereby alleviating renal tubular cell apoptosis. Collectively, these studies demonstrate that KP1 is a promising therapeutic agent for AKI by directly targeting and preserving mitochondrial integrity. Our findings also lay the groundwork for developing novel therapeutic strategies to treat diseases associated with mitochondrial dysfunction.