首页|TRPM2 Mediates Hepatic Ischemia-Reperfusion Injury via Ca2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression

TRPM2 Mediates Hepatic Ischemia-Reperfusion Injury via Ca2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression

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Hepatic ischemia-reperfusion(IR)injury is a serious clinical problem that complicates liver resection and transplantation.Despite recent advances in understanding of the pathophysiology of hepatic IR injury,effective interventions and therapeutics are still lacking.Here,we examined the role of transient receptor potential melastatin 2(TRPM2),a Ca2+-permeable,non-selective cation channel,in mediating hepatic IR injury.Our data showed that TRPM2 deficiency attenuated IR-induced liver dysfunction,inflammation,and cell death in mice.Moreover,RNA sequencing analysis indicated that TRPM2-induced IR injury occurs via ferroptosis-related pathways.Consistently,as a ferroptosis inducer,(1S,3R)-RSL3 treatment induced mitochondrial dysfunction in hepatocytes and a TRPM2 inhibitor suppressed this.Interestingly,TRPM2-mediated calcium influx caused mitochondrial calcium accumulation via the mitochondrial Ca2+-selective uniporter and increased the expression level of arachidonate 12-lipoxygenase(ALOX12),which results in mitochondrial lipid peroxidation during hepatic IR injury.Furthermore,hepatic IR injury-induced ferroptosis was obviously relieved by a TRPM2 inhibitor or calcium depletion,both in vitro and in vivo.Collectively,these findings demonstrate a crucial role for TRPM2-mediated ferroptosis in hepatic IR injury via increased Ca2+-induced ALOX12 expression,indicating that pharmacological inhibition of TRPM2 may provide an effective therapeutic strategy for hepatic IR injury-related diseases,such as during liver resection and transplantation.

Cheng Zhong、Jing Yang、Yiyin Zhang、Xiaoxiao Fan、Yang Fan、Ning Hua、Duguang Li、Shengxi Jin、Yirun Li、Peng Chen、Yongle Chen、Xiaobo Cai、Yi Zhang、Linhua Jiang、Wei Yang、Peilin Yu、Hui Lin

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Department of General Surgery,Sir Run Run Shaw Hospital,School of Medicine,Zhejiang University,Hangzhou,P.R.China

Department of Toxicology and Department of Medical Oncology of Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,P.R.China

Department of Physiology and Pathophysiology and Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province,Xinxiang Medical University,453003 Xinxiang,Henan,P.R.China

Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310000,P.R.China

School of Biomedical Sciences,Faculty of Biological Sciences,University of Leeds,LS2 9JT Leeds,UK

Zhejiang Engineering Research Center of Cognitive Healthcare,Sir Run Run Shaw Hospital,School of Medicine,Zhejiang University,Hangzhou 310020,P.R.China

College of Biomedical Engineering and Instrument Science,Zhejiang University,Hangzhou 310058,P.R.China

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国家重点研发计划Zhejiang Province Key Research and Development ProjectZhejiang Province Key Research and Development Project国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金浙江省自然科学基金Zhejiang Engineering Research Center of Cognitive HealthcareNational Key Scientific Instrument and Equipment Development Project中国博士后科学基金

2017YFC01108022020C0105920208203010831872796818740593207110282102105LQ22H1600172017E10011818278042021M702825

2024

10.34133/research.0159

研究(英文)

研究(英文)

CSTPCD
ISSN：
年,卷(期)：2024.2024(1)
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