Mitochondrial DNA regulation of hepatic ischemia-reperfusion injury and intervention strategies.

BACKGROUND: Hepatic ischemia-reperfusion injury (IRI) is a common pathological process in liver surgery, which seriously affects the prognosis of patients. Its core mechanism is closely related to a vicious cycle triggered by an imbalance in mitochondrial quality control and abnormal release of mitochondrial DNA (mtDNA). MAIN BODY: When mitochondria are damaged by ischemia and hypoxia, dysfunction in key quality control processes—including mitochondrial autophagy, which clears damaged components, mitochondrial dynamics (fusion/fission) that regulate morphology, and the formation of mitochondrial-derived vesicles (MDVs)—prevents the effective isolation or elimination of damage. This leads to increased mitochondrial membrane permeability, facilitating the release of mtDNA into the cytoplasm. Released mtDNA serves as a key signaling molecule that directly drives various forms of programmed cell death. It promotes apoptosis by activating the cGAS-STING pathway. As a damage-associated molecular pattern (DAMP), it can also trigger NLRP3 inflammasome-mediated and GSDMD-mediated pyroptosis. Additionally, it promotes ferroptosis by amplifying oxidative stress and disrupting iron metabolism. Ultimately, mtDNA aggravates uncontrolled innate immune responses and cell death through inflammatory pathways like cGAS-STING, NLRP3, and TLR9, further amplifying tissue injury. Therefore, preventing mtDNA leakage or inhibiting its downstream inflammatory and cell death pathways have emerged as key approaches for mitigating hepatic IRI. SHORT CONCLUSION: In hepatic IRI, abnormal release of mtDNA activates inflammation, forming a vicious cycle of "injury -mtDNA release - immunity". Intervention strategies for this process have therapeutic potential. Meanwhile, dynamic monitoring of circulating mtDNA can serve as a non-invasive biomarker for evaluating the status and prognosis of the graft. In the future, integrating technologies such as mitochondrial genomics and immunometabolomics will drive this field towards precision treatment.