Abstract
Acute kidney injury (AKI) is a prevalent clinical syndrome with high morbidity and mortality. Accumulating studies suggest mitochondrial dysfunction as the typical characteristics and key process of AKI, but the underlying mechanism remains elusive. The YME1-like 1 (YME1L1) ATPase, an inner mitochondrial membrane protein, is screened and identified to be downregulated in renal tubular epithelial cells of various mouse models and patients of AKI. Dramatically, restoration of YME1L1 expression significantly alleviates cisplatin-induced AKI and subsequent chronic kidney disease (CKD) through attenuating mitochondrial dysfunction via maintaining optic atrophy 1 (OPA1)-mediated mitochondrial energy metabolism homeostasis. Mechanistically, the upregulated expression of sterol regulatory element binding transcription factor 1c (SREBP1c) is demonstrated to be responsible for cisplatin-mediated transcriptional inhibition of YME1L1 via directly binding to its promoter region. Moreover, cisplatin-induced methyltransferase-like 3 (METTL3)-mediated m6A modification enhances SREBP1c mRNA stability, thereby upregulating its expression. Notably, both depletion of SREBP1c and renal tubule-specific overexpression of YME1L1 markedly ameliorate cisplatin-induced AKI and its transition to CKD. Taken together, these findings suggest that METTL3-mediated SREBP1c upregulation contributes to AKI and its progression to CKD through disrupting mitochondrial energy metabolism via transcriptionally suppressing YME1L1. Targeting the SREBP1c/YME1L1 signaling may serve as a novel therapeutic strategy against AKI.