Ceramide(d18:1/18:1)-NDUFA6 interaction inactivates respiratory complex I to attenuate oxidative-stress-driven pathogenesis in liver ischemia/reperfusion injury
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.
Authors
- Hanbiao Liang
- Baoxiong Zhuang
- Jieyuan Li (ORCID: https://orcid.org/0000-0003-3666-9796)
- Leyi Liao
- Ruijuan Xu (ORCID: https://orcid.org/0000-0003-1208-6502)
- Jie Zhou (ORCID: https://orcid.org/0000-0002-3626-4732)
- Cuiting Liu (ORCID: https://orcid.org/0000-0002-6893-0787)
- Cungui Mao (ORCID: https://orcid.org/0000-0002-1330-1887)
- Wei Wang
- B. Wang (ORCID: https://orcid.org/0000-0002-9157-360X)
- Ping Chen (ORCID: https://orcid.org/0000-0002-9940-4528)
- Qingping Li (ORCID: https://orcid.org/0000-0001-7526-2425)
- Yiyi Li (ORCID: https://orcid.org/0000-0003-0684-7467)
- Xuming Mo
- Minghui Zeng (ORCID: https://orcid.org/0000-0002-6055-6495)
- Chuanjiang Li (ORCID: https://orcid.org/0000-0002-3583-2881)
- Lei Yang (ORCID: https://orcid.org/0000-0002-2882-5560)
- Xuesong Deng
- Pengxiang Huang (ORCID: https://orcid.org/0000-0002-3106-327X)
- Xianqiu Wu
Institutions
- State University of New York (US)
- Southern University of Science and Technology (CN)
- Nanfang Hospital (CN)
- First People's Hospital of Foshan (CN)
- Shenzhen University Health Science Center (CN)
- Shenzhen Second People's Hospital (CN)
- Shenzhen Third People’s Hospital (CN)
- Southern Medical University (CN)
- Stony Brook University (US)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1172/jci.insight.187083
- Citations
- 1
- Primary Topic
- Sphingolipid Metabolism and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Natural Science Foundation of China
- Southern Medical University
- Nanfang Hospital
- Basic and Applied Basic Research Foundation of Guangdong Province
- H2020 European Research Council