Therapeutic remodeling of the ceramide backbone prevents kidney injury

作者：Rebekah J. Nicholson, Luis Cedeño-Rosario, J. Alan Maschek, Trevor Lonergan, Jonathan G. Van Vranken, Angela Kruse, Chris Stubben, Liping Wang, Deborah Stuart, Queren Apuque Alcantara, Mónica P. Revelo, Kate Rutter, Mayette Pahulu, Jacob Taloa, Xiao Wu, Juwan Kim, Juna Kim, Isaac E. Hall, Amanda J. Clark, Samir M. Parikh, Jeffrey M. Spraggins, Donna L. Romero, Jeremy T. Blitzer, Steven P. Gygi, Jared Rutter, William L. Holland, Nirupama Ramkumar, Scott A. Summers · 发表于：Cell Metabolism · 年份：2025 · DOI：10.1016/j.cmet.2025.10.006 · 被引用次数：6 · 研究领域：Sphingolipid Metabolism and Signaling、Biomedical Research and Pathophysiology、Intracerebral and Subarachnoid Hemorrhage Research

Perturbation of proximal tubule (PT) lipid metabolism fuels the pathological features of acute kidney injury (AKI). We found that AKI induced biosynthesis of lipotoxic ceramides within PTs in humans and mice and that urine ceramides predicted disease severity in children and adults. Mechanistic studies in primary PTs, which included a thermal proteomic profiling screen for ceramide effectors, revealed that ceramides altered assembly of the mitochondrial contact site and cristae-organizing system (MICOS) and respiratory supercomplexes, leading to acute disruption of cristae architecture, mitochondrial morphology, and respiration. These ceramide actions were dependent on the presence of the 4,5-trans double bond inserted by dihydroceramide desaturase 1 (DES1). Genetically ablating DES1 preserved mitochondrial integrity and prevented kidney injury in mice following bilateral ischemia reperfusion. Moreover, novel DES1 inhibitors that are attractive clinical drug candidates phenocopied the DES1 knockouts. These studies describe a new, therapeutically tractable mechanism underlying PT mitochondrial damage in AKI.