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

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). 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. 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.