Exploring the role of Mitoferrin-1 in Ferroptosis and mitochondrial damage in acute ischemic stroke.

Abstract

The pathogenesis of acute ischemic stroke (AIS) is complex, with limited therapeutic options available during the acute phase. Therefore, investigating the underlying mechanisms of AIS is critical. Ferroptosis has been implicated in AIS-induced damage; however, its precise molecular mechanisms remain elusive. In this study, we explored the role of Mitoferrin-1 (Mfrn1) in AIS using a combination of in vitro and in vivo models, including RNA sequencing, RNA interference (RNAi), Adeno-associated virus (AAV9) injection, gene overexpression, and ferroptosis detection. Our results demonstrated that Mfrn1 expression, mitochondrial iron levels, mitochondrial injury, and ferroptosis were significantly increased in AIS models. Knockdown of Mfrn1 attenuated ferroptosis and oxygen-glucose deprivation/reperfusion (OGD/R)-induced injury, whereas overexpression of Mfrn1 had the opposite effect. Similarly, silencing Mfrn1 decreased mitochondrial iron accumulation and injury, while its overexpression exacerbated both. In middle cerebral artery occlusion/reperfusion (MCAO/R) rats, silencing Mfrn1 suppressed ferroptosis, reduced AIS-related injury, lowered mitochondrial iron levels, and mitigated mitochondrial damage. These findings suggest that Mfrn1 exacerbates AIS damage by promoting mitochondrial iron accumulation and injury. This study highlights Mfrn1 as a potential therapeutic target for AIS.