Mitochondrial Ferritin Overexpression Attenuates Ferroptosis and Mitochondrial Dysfunction by Reducing VDAC1 to Relieve MI/RI-Induced Damage.

Ischaemic cardiomyopathy is becoming one of the most prevalent cardiovascular diseases among the global elderly population. However, the underlying molecular mechanisms remain incompletely understood. Our previous study demonstrated that VDAC1 plays a significant role in MI/RI. Furthermore, FTMT plays a pivotal role in iron metabolism. However, the precise molecular functions of VDAC1 and FTMT in MI/RI remain to be elucidated. In vitro H9c2 cells A/R and in vivo SD rat MI/RI models were constructed. The present study reports that VDAC1 levels were increased and FTMT levels were decreased in A/R. The overexpression of VDAC1 resulted in an exacerbation of the A/R-induced injury, characterised by an increase in oxidative stress, a reduction in the GSH/GSSG ratio, the formation of reactive oxygen species, elevated levels of lipid peroxidation, and the deposition of iron. In contrast, FTMT overexpression reversed these alterations and mitigated mitochondrial dysfunction by downregulating VDAC1, PTGS2 levels, upregulating GPX4 levels, inhibiting MPTP over-opening and stabilising MMP. Additionally, knockdown of VDAC1 alleviated A/R-induced ferroptosis. In vivo experiments showed that overexpression of FTMT improved cardiac function in rats, as evidenced by the reduction of MI/RI-induced serum CK-MB, LDH and Fe(2+) content and the shrinkage of myocardial infarction area. Moreover, HE, DHE staining and TEM observations showed that the overexpression of FTMT ameliorated MI/RI-induced myocardial tissue and mitochondrial damage. Furthermore, the overexpression of FTMT was found to inhibit MI/RI-induced ferroptosis. In general, our study is the first to demonstrate that FTMT overexpression alleviates ferroptosis and mitochondrial dysfunction by regulating VDAC1, thereby reducing MI/RI injury.