Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
MARCH5-mediated MIEF2 ubiquitination and degradation contribute to gigantol to against hepatic steatosis and mitochondrial fission in alcoholic liver disease.
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Wu Yangsheng, Dai Shijie, Li Zheming, Xu Lanman, Zhang YuJia, Qiu Jiannan, Chen Lin, Lin Yiyou, Mao Mingjiang, Xu Jianglei, Li Shouye, Yuan Xiaofeng, Dou Xiaobing
Аннотация
BACKGROUND: Alcoholic liver disease (ALD) is among the most prevalent health issues caused by chronic alcohol consumption. The mitochondrial E3 ligase Membrane Associated Ring-CH-type Finger 5 (MARCH5, also known as MITOL) is involved in mitochondrial fission in ALD. Gigantol (Gig) has been reported to alleviate oxidative dysfunction and inflammation in liver injury, but its effects on ALD and the mechanisms underlying these effects are not completely comprehended. This study aimed to explore the potential effects and mechanisms of Gig against ALD.
METHODS: In this research, we explored the impacts of Gig on ethanol-treated zebrafish larvae, C57BL/6 mice, and AML12 cells. In vitro and in vivo gain- and loss-of-function experiments were employed to investigate the functions of MARCH5 and MIEF2 in ALD and the mechanisms underlying their functions.
RESULTS: Gig alleviated hepatic steatosis, cell death, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial fission in both animal and cell models. Functionally, MIEF2 depletion potently repressed fatty acid synthesis, cell apoptosis and mitochondrial fission in vitro, at least in part by inhibiting the ROS/JNK/CHOP pathway. Moreover, overexpression of MIEF2 effectively reversed the reduction in lipid accumulation, cell death, mitochondrial fission, and mitochondria-associated membrane (MAMs) formation caused by MARCH5 overexpression. Mechanistically, MARCH5 directly interacted with MIEF2 to cause its ubiquitination and proteasomal degradation, thereby regulating mitochondrial dynamics in AML12 cells. Additionally, liver-specific MARCH5 knockdown markedly aggravated liver injury induced by an ethanol-containing diet. Importantly, liver-specific knockdown of MARCH5 in ALD model mice abolished the protective effects of Gig on the liver, partly through the activation of the MIEF2/JNK/CHOP pathway.
CONCLUSION: These results suggest that Gig may protect against hepatic steatosis and mitochondrial fission in ALD by targeting MARCH5 to mediate ubiquitination and degradation of MIEF2, which lays the foundation for research on the effects of Gig against liver illnesses.
METHODS: In this research, we explored the impacts of Gig on ethanol-treated zebrafish larvae, C57BL/6 mice, and AML12 cells. In vitro and in vivo gain- and loss-of-function experiments were employed to investigate the functions of MARCH5 and MIEF2 in ALD and the mechanisms underlying their functions.
RESULTS: Gig alleviated hepatic steatosis, cell death, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial fission in both animal and cell models. Functionally, MIEF2 depletion potently repressed fatty acid synthesis, cell apoptosis and mitochondrial fission in vitro, at least in part by inhibiting the ROS/JNK/CHOP pathway. Moreover, overexpression of MIEF2 effectively reversed the reduction in lipid accumulation, cell death, mitochondrial fission, and mitochondria-associated membrane (MAMs) formation caused by MARCH5 overexpression. Mechanistically, MARCH5 directly interacted with MIEF2 to cause its ubiquitination and proteasomal degradation, thereby regulating mitochondrial dynamics in AML12 cells. Additionally, liver-specific MARCH5 knockdown markedly aggravated liver injury induced by an ethanol-containing diet. Importantly, liver-specific knockdown of MARCH5 in ALD model mice abolished the protective effects of Gig on the liver, partly through the activation of the MIEF2/JNK/CHOP pathway.
CONCLUSION: These results suggest that Gig may protect against hepatic steatosis and mitochondrial fission in ALD by targeting MARCH5 to mediate ubiquitination and degradation of MIEF2, which lays the foundation for research on the effects of Gig against liver illnesses.