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

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

doi:10.1172/jci.insight.187083

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

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

Stony Brook University

Southern Medical University
Southern University of Science and Technology
Shenzhen University
First People's Hospital of Foshan
Stony Brook University

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English
Article number	e187083
Journal	JCI Insight
Volume	10
Issue number	10
DOIs	https://doi.org/10.1172/jci.insight.187083
State	Published - May 2025

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10.1172/jci.insight.187083

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Wang, K., Liao, L., Liang, H., Huang, P., Li, Q., Zhuang, B., Xie, C., Mo, X., Deng, X., Li, J., Lei, Y., Zeng, M., Mao, C., Xu, R., Liu, C., Wu, X., Zhou, J., Wang, B., Li, Y., & Li, C. (2025). Ceramide(d18:1/18:1)-NDUFA6 interaction inactivates respiratory complex I to attenuate oxidative-stress-driven pathogenesis in liver ischemia/ reperfusion injury. JCI Insight, 10(10), Article e187083. https://doi.org/10.1172/jci.insight.187083

@article{03f180dd83b14f78b4d2b3201832b8dd,

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2025, Wang et al.",

year = "2025",

month = may,

doi = "10.1172/jci.insight.187083",

language = "English",

volume = "10",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "American Society for Clinical Investigation",

number = "10",

}

Wang, K, Liao, L, Liang, H, Huang, P, Li, Q, Zhuang, B, Xie, C, Mo, X, Deng, X, Li, J, Lei, Y, Zeng, M, Mao, C, Xu, R, Liu, C, Wu, X, Zhou, J, Wang, B, Li, Y & Li, C 2025, 'Ceramide(d18:1/18:1)-NDUFA6 interaction inactivates respiratory complex I to attenuate oxidative-stress-driven pathogenesis in liver ischemia/ reperfusion injury', JCI Insight, vol. 10, no. 10, e187083. https://doi.org/10.1172/jci.insight.187083

TY - JOUR

T1 - Ceramide(d18:1/18:1)-NDUFA6 interaction inactivates respiratory complex I to attenuate oxidative-stress-driven pathogenesis in liver ischemia/ reperfusion injury

AU - Wang, Kai

AU - Liao, Leyi

AU - Liang, Hanbiao

AU - Huang, Pengxiang

AU - Li, Qingping

AU - Zhuang, Baoxiong

AU - Xie, Chen

AU - Mo, Xiangyue

AU - Deng, Xuesong

AU - Li, Jieyuan

AU - Lei, Yang

AU - Zeng, Minghui

AU - Mao, Cungui

AU - Xu, Ruijuan

AU - Liu, Cuiting

AU - Wu, Xianqiu

AU - Zhou, Jie

AU - Wang, Biao

AU - Li, Yiyi

AU - Li, Chuanjiang

PY - 2025/5

Y1 - 2025/5

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105006580484

U2 - 10.1172/jci.insight.187083

DO - 10.1172/jci.insight.187083

M3 - Article

C2 - 40244698

SN - 2379-3708

VL - 10

JO - JCI Insight

JF - JCI Insight

IS - 10

M1 - e187083

ER -

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

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