Mitochondrial DNA Is a Vital Driving Force in Ischemia-Reperfusion Injury in Cardiovascular Diseases

Abstract

According to the latest Global Burden of Disease Study, cardiovascular disease (CVD) is the leading cause of death, and ischemic heart disease and stroke are the cause of death in approximately half of CVD patients. In CVD, mitochondrial dysfunction following ischemia-reperfusion (I/R) injury results in heart failure. The proper functioning of oxidative phosphorylation (OXPHOS) and the mitochondrial life cycle in cardiac mitochondria are closely related to mitochondrial DNA (mtDNA). Following myocardial I/R injury, mitochondria activate multiple repair and clearance mechanisms to repair damaged mtDNA. When these repair mechanisms are insufficient to restore the structure and function of mtDNA, irreversible mtDNA damage occurs, leading to mtDNA mutations. Since mtDNA mutations aggravate OXPHOS dysfunction and affect mitophagy, mtDNA mutation accumulation leads to leakage of mtDNA and proteins outside the mitochondria, inducing an innate immune response, aggravating cardiovascular injury, and leading to the need for external interventions to stop or slow the disease course. On the other hand, mtDNA released into the circulation after cardiac injury can serve as a biomarker for CVD diagnosis and prognosis. This article reviews the pathogenic basis and related research findings of mtDNA oxidative damage and mtDNA leak-triggered innate immune response associated with I/R injury in CVD and summarizes therapeutic options that target mtDNA.

HJ11 decoction restrains development of myocardial ischemia-reperfusion injury in rats by suppressing ACSL4-mediated ferroptosis

“…Interestingly, this research demonstrated that HJ11 decoction could mitigate the apoptosis of cardiomyocytes in the myocardial I/R injury rat model. CK-MB and LDH are sensitive factors for the evaluation of myocardial I/R injury ( Liu et al, 2022 ). Aberrant expression of CK-MB and LDH can suppress the antioxidant potential of cardiomyocytes ( Liu et al, 2020 ).…”

OGG1 in the Kidney: Beyond Base Excision Repair

“…They also found that the accumulation of 8-oxoG in mtDNA, rather than in nuclear DNA, may be involved in renal tubular cell injury and other pathological reactions caused by renal ischemia-reperfusion injury. In cardiac ischemia-reperfusion injury model studies, mtDNA damage repaired by OGG1 base excision seemed to have no significant effect on cardiac function [123,124]. In an ischemia-reperfusion model, the DNA repair function of OGG1 is inhibited under oxidative stress, and the upregulated OGG1 levels may also have other transcriptional regulatory effects, which require further study.…”

Mitochondrial dysfunctions induce PANoptosis and ferroptosis in cerebral ischemia/reperfusion injury: from pathology to therapeutic potential

“…Mitochondria are the only organelle possessing their circular genome, which is 16.6 kb in mammals, encoding 13 subunits that are essential in the maintenance and regulation of mitochondrial functions, such as encoding essential proteins of ETC and OXPHOS system ( Liu H. et al, 2022 ). As mtDNA exists within the mitochondrial matrix or attached to the IMM, it can be easily damaged by free radicals produced by the respiratory chain.…”