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Accumulating studies suggest mitochondrial dysfunction as the typical characteristics and key process of AKI, but the underlying mechanism remains elusive. The YME1\u2010like 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\u2010induced AKI and subsequent chronic kidney disease (CKD) through attenuating mitochondrial dysfunction via maintaining optic atrophy 1 (OPA1)\u2010mediated mitochondrial energy metabolism homeostasis. Mechanistically, the upregulated expression of sterol regulatory element binding transcription factor 1c (SREBP1c) is demonstrated to be responsible for cisplatin\u2010mediated transcriptional inhibition of YME1L1 via directly binding to its promoter region. Moreover, cisplatin\u2010induced methyltransferase\u2010like 3 (METTL3)\u2010mediated m6A modification enhances SREBP1c mRNA stability, thereby upregulating its expression. Notably, both depletion of SREBP1c and renal tubule\u2010specific overexpression of YME1L1 markedly ameliorate cisplatin\u2010induced AKI and its transition to CKD. Taken together, these findings suggest that METTL3\u2010mediated 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.<\/jats:p>","DOI":"10.1002\/advs.202412233","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T14:49:53Z","timestamp":1734360593000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["SREBP1c\u2010Mediated Transcriptional Repression of YME1L1 Contributes to Acute Kidney Injury by Inducing Mitochondrial Dysfunction in Tubular Epithelial Cells"],"prefix":"10.1002","volume":"12","author":[{"given":"Wang","family":"Xin","sequence":"first","affiliation":[{"name":"Department of Nephrology Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease Chongqing Clinical Research Center of Kidney and Urology Diseases Xinqiao Hospital Army Medical University (Third Military Medical University)  Chongqing 400037 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