Mitochondria-derived H 2 O 2 triggers liver regeneration via FoxO3a signaling pathway after partial hepatectomy in mice

Cell Death & Disease · 13 authors, 11 centres

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TL;DR

Using a mouse partial hepatectomy model, this study found that mitochondria-derived hydrogen peroxide (H2O2) increases early and is essential for triggering liver regeneration, acting through the Akt/Erk/FoxO3a/p27 signaling pathway.

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This preclinical study investigated the role of mitochondria-derived hydrogen peroxide (H2O2) in liver regeneration (LR) after partial hepatectomy (PHx) in mice. Using liver-specific genetic modifications (mCAT overexpression to scavenge mitochondrial H2O2, CRISPR-Cas9 to knockdown FoxO3a) and pharmacological interventions, the researchers demonstrated that mitochondrial H2O2 increases early post-PHx and is required for normal LR. Scavenging mitochondrial H2O2 compromised LR, while inhibition of NADPH oxidases had no effect. The mechanism involves H2O2-mediated activation of Akt and Erk, leading to phosphorylation and nuclear exclusion of the transcription factor FoxO3a, which reduces expression of the cell cycle inhibitor p27. Limitations include not testing if enhancing mitochondrial H2O2 production accelerates LR, not fully exploring upstream regulators of FoxO3a, and not evaluating mitochondrial function. The findings suggest that improper antioxidative therapy could impair liver recovery.

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other

SPECIALTY

preclinical research

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AI pipeline

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100% · A

ORIGINAL PAPER

PMC10050396

Mitochondria-derived H 2 O 2 triggers liver regeneration via FoxO3a signaling pathway after partial hepatectomy in mice

Cell Death & Disease

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ABSTRACT

Reactive oxygen species (ROS) can induce oxidative injury and are generally regarded as toxic byproducts, although they are increasingly recognized for their signaling functions. Increased ROS often accompanies liver regeneration (LR) after liver injuries, however, their role in LR and the underlying mechanism remains unclear. Here, by employing a mouse LR model of partial hepatectomy (PHx), we found that PHx induced rapid increases of mitochondrial hydrogen peroxide (H 2 O 2 ) and intracellular H 2 O 2 at an early stage, using a mitochondria-specific probe. Scavenging mitochondrial H 2 O 2 in mice with liver-specific overexpression of mitochondria-targeted catalase (mCAT) decreased intracellular H 2 O 2 and compromised LR, while NADPH oxidases (NOXs) inhibition did not affect intracellular H 2 O 2 or LR, indicating that mitochondria-derived H 2 O 2 played an essential role in LR after PHx. Furthermore, pharmacological activation of FoxO3a impaired the H 2 O 2 -triggered LR, while liver-specific knockdown of FoxO3a by CRISPR-Cas9 technology almost abolished the inhibition of LR by overexpression of mCAT, demonstrating that FoxO3a signaling pathway mediated mitochondria-derived H 2 O 2 triggered LR after PHx. Our findings uncover the beneficial roles of mitochondrial H 2 O 2 and the redox-regulated underlying mechanisms during LR, which shed light on potential therapeutic interventions for LR-related liver injury. Importantly, these findings also indicate that improper antioxidative intervention might impair LR and delay the recovery of LR-related diseases in clinics.

CITATION EXPORT

Hua Bai, Cong-Wen Fang, Ying Shi et al.. Mitochondria-derived H2O2 triggers liver regeneration via FoxO3a signaling pathway after partial hepatectomy in mice. Cell Death & Disease. (2023). https://doi.org/10.1038/s41419-023-05744-w

AUTHORS

13 · 11 CENTRES

Hua Bai, Cong-Wen Fang, Ying Shi, Song Zhai, An Jiang, Ying-Na Li, Lin Wang, Qi-Ling Liu, Geng-Yao Zhou, Jia-Hao Cao, Jia Li, Xue-Kang Yang, Xu-Jun Qin

1grid.440588.50000 0001 0307 1240Frontiers Science Center for Flexible Electronics, Xi’an Institute of Flexible Electronics (IFE) and Xi’an Institute of Biomedical Materials & Engineering, Northwestern Polytechnical University, Xi’an, 710072 China
2grid.233520.50000 0004 1761 4404Department of Nutrition and Food Hygiene, School of Preventive Medicine, The Fourth Military Medical University, Xi’an, 710032 China
3grid.449637.b0000 0004 0646 966XSchool of Public Health, Shaanxi University of Chinese Medicine, Xianyang, 712046 China
4Weiyang District Center for Disease Control and Prevention, Xi’an, 710016 China
5grid.43169.390000 0001 0599 1243Department of Infectious Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004 China
6grid.43169.390000 0001 0599 1243Department of General Surgery Ward 4, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, 710004 China
7People’s Hospital of Zhuhai High-tech Industrial Development Zone, Zhuhai, 519085 China
8grid.233520.50000 0004 1761 4404Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032 China
9grid.233520.50000 0004 1761 4404Key Laboratory of Aerospace Medicine of Ministry of Education, School of Aerospace Medicine, The Fourth Military Medical University, Xi’an, 710032 China
10grid.233520.50000 0004 1761 4404Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, 710032 China
11grid.440588.50000 0001 0307 1240Key Laboratory for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an, 710072 China