TRPM2 Mediates Hepatic Ischemia–Reperfusion Injury via Ca ²⁺ -Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression

Abstract

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 Ca 2+ -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 Ca 2+ -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 Ca 2+ -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.

Hepatocellular SETDB1 Regulates Hepatic Ischemia-Reperfusion Injury through Targeting Lysine Methylation of ASK1 Signal

“…HIRI, a multifactorial pathological process, exerts an important impact on the prognosis of liver surgery, influencing its outcomes [ 15 ]. Following comprehensive functional studies, we have recognized SETDB1 as a promising therapeutic target for HIRI treatment.…”

Coumarin Glycosides Reverse Enterococci-Facilitated Enteric Infections

“…Tm 15E475 or enterococcal strains [wild-type, empty vector (EV), bgl -OE#1, and bgl -OE#2] was extracted using the SteadyPure Universal RNA Extraction Kit. Reverse transcription of 1 μg of extracted RNA was performed using the Evo M-MLV Mix Kit following the manufacturer’s protocol and a previous report [ 48 ]. Relative mRNA levels of VGs related to T3SS-1 were normalized to the expression of the housekeeping gene ( rpoD ) in S .…”

The TRPM2 ion channel regulates metabolic and thermogenic adaptations in adipose tissue of cold-exposed mice

“…Thus, from the literature, TRPM2 can likely play distinct roles, by regulating both the endocrine system and metabolism in peripheral tissues. Regarding liver, TRPM2 has been shown to be relevant in oxidative stress conditions ( 26 ) and in hepatic Ischemia-Reperfusion injury ( 27 ). However, as mentioned above, the role played by TRPM2 in adipogenesis and thermogenic response has not been established yet; nevertheless, TRPM2 expression in both BAT and WAT has been documented ( 28 ).…”