Ceramide(d18:1/18:1)-NDUFA6 interaction inactivates respiratory complex I to attenuate oxidative-stress-driven pathogenesis in liver ischemia/reperfusion injury

作者：Wei Wang, Leyi Liao, Hanbiao Liang, Pengxiang Huang, Qingping Li, Baoxiong Zhuang, Chen Xie, Xuming Mo, Xuesong Deng, Jieyuan Li, Lei Yang, Minghui Zeng, Cungui Mao, Ruijuan Xu, Cuiting Liu, Xianqiu Wu, Jie Zhou, B. Wang, Yiyi Li, Chuanjiang Li · 发表于：JCI Insight · 年份：2025 · DOI：10.1172/jci.insight.187083 · 被引用次数：4 · 研究领域：Sphingolipid Metabolism and Signaling、Eicosanoids and Hypertension Pharmacology、Biomedical Research and Pathophysiology

Oxidative stress driven by malfunctioning respiratory complex I (RC-I) is a crucial pathogenic factor in liver ischemia/reperfusion (I/R) injury. This study investigated the role of alkaline ceramidase 3 (ACER3) and its unsaturated long-chain ceramide (CER) substrates in regulating liver I/R injury through RC-I. Our findings demonstrated that I/R upregulated ACER3 and decreased unsaturated long-chain CER levels in human and mouse livers. Both global and hepatocyte-specific Acer3 ablation, as well as treatment with CER(d18:1/18:1), led to a significant increase in CER(d18:1/18:1) levels in the liver, which mitigated the I/R-induced hepatocyte damage and inflammation in mice. Mechanistically, ACER3 modulated CER(d18:1/18:1) levels in mitochondria-associated membranes and the endoplasmic reticulum (ER), thereby influencing the transport of CER(d18:1/18:1) from the ER to mitochondria. Acer3 ablation and CER(d18:1/18:1) treatment elevated CER(d18:1/18:1) in mitochondria, where CER(d18:1/18:1) bound to the RC-I subunit NDUFA6 to inactivate RC-I and reduced reactive oxygen species production in the I/R-injured mouse liver. These findings underscore the role of the CER(d18:1/18:1)-NDUFA6 interaction in suppressing RC-I-mediated oxidative-stress-driven pathogenesis in liver I/R injury.