Mdivi-1 promotes lipid droplets-mitochondria contact and ameliorates cardiac lipotoxicity in high-fat diet-fed mice

Myocardial lipid overload triggers excessive mitochondrial fission and impairs lipid droplets (LDs)-mitochondrial contact, thereby contributing to the development of lipotoxic cardiomyopathy. This study aimed to investigate whether the mitochondrial fission inhibitor Mdivi-1 could alleviate cardiac lipotoxicity by restoring LDs-mitochondria contact in high-fat diet (HFD)-fed mice. In vivo, male C57BL/6 HFD-fed mice were intraperitoneally injected with the mitochondrial fission inhibitor Mdivi-1 for 8 weeks. In vitro, H9C2 cardiomyoblasts were exposed to palmitic acid (PA), followed by treatment with Mdivi-1. Comprehensive assessments of cardiac function, along with molecular, biochemical, histological, cellular, and morphological analyses were performed. Results showed that Mdivi-1 treatment exerted protective effects against metabolic disorder and cardiac dysfunction in HFD-fed mice. Mdivi-1 promoted LDs-mitochondria contact by upregulating Plin2 and Plin5 expression, thereby alleviating cardiac lipotoxicity. Furthermore, PA disrupted the LDs-mitochondrial contact and induced lipotoxicity in a dose-dependent manner in H9C2 cardiomyoblasts. Mdivi-1 effectively inhibited PA-induced mitochondrial fission, restored LDs-mitochondrial contact, and facilitated the transport of fatty acids from LDs to the mitochondria for fatty acid oxidation in H9C2 cells. In conclusion, our study identifies Mdivi-1 as a novel cardioprotective agent capable of ameliorating cardiac lipotoxicity and promoting LDs-mitochondria contact.