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

IF 6.3 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

JCI insight Pub Date : 2025-04-17 eCollection Date: 2025-05-22 DOI:10.1172/jci.insight.187083

Kai Wang, Leyi Liao, Hanbiao Liang, Pengxiang Huang, Qingping Li, Baoxiong Zhuang, Chen Xie, Xiangyue Mo, Xuesong Deng, Jieyuan Li, Yang Lei, Minghui Zeng, Cungui Mao, Ruijuan Xu, Cuiting Liu, Xianqiu Wu, Jie Zhou, Biao Wang, Yiyi Li, Chuanjiang Li

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引用次数: 0

Abstract

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.

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神经酰胺(d18:1/18:1)-Ndufa6相互作用使呼吸复合体I失活，减轻肝脏缺血/再灌注损伤中氧化应激驱动的发病机制。

由呼吸复合体I功能障碍（RC-I）引起的氧化应激是肝脏缺血再灌注损伤的重要致病因素。本研究探讨碱性神经酰胺酶3 （ACER3）及其不饱和长链神经酰胺（CER）底物通过RC-I调节肝脏I/R损伤的作用。我们的研究结果表明，I/R上调ACER3/ ACER3，并降低人类和小鼠肝脏中不饱和长链CER水平。整体和肝细胞特异性Acer3消融以及CER治疗（d18:1/18:1）均可导致肝脏中CER（d18:1/18:1）水平显著升高，从而减轻小鼠I/ r诱导的肝细胞损伤和炎症。在机制上，Acer3调节线粒体相关膜和内质网（ER）中的CER（d18:1/18:1）水平，从而影响CER（d18:1/18:1）从ER到线粒体的运输。Acer3消融和CER（d18:1/18:1）治疗可提高线粒体中的CER(d18:1/18:1)，其中CER（d18:1/18:1）与RC-I亚基Ndufa6结合，使RC-I失活，并减少I/ r损伤小鼠肝脏中的活性氧产生。这些发现强调了CER(d18:1/18:1)-Ndufa6相互作用在抑制肝I/R损伤中rc -I介导的氧化应激驱动的发病机制中的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

JCI insight Medicine-General Medicine

CiteScore

13.70

自引率

1.20%

发文量

543

审稿时长

6 weeks

期刊介绍： JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.