Mst1 Knockout Alleviates Mitochondrial Fission and Mitigates Left Ventricular Remodeling in the Development of Diabetic Cardiomyopathy

Abstract

The disruption of mitochondrial dynamics is responsible for the development of diabetic cardiomyopathy (DCM). However, the mechanisms that regulate the balance of mitochondrial fission and fusion are not well-understood. Wild-type, Mst1 transgenic and Mst1 knockout mice were induced with experimental diabetes by streptozotocin injection. In addition, primary neonatal cardiomyocytes were isolated and cultured to simulate diabetes to explore the mechanisms. Echocardiograms and hemodynamic measurements revealed that Mst1 knockout alleviated left ventricular remodeling and cardiac dysfunction in diabetic mice. Mst1 knockdown significantly decreased the number of TUNEL-positive cardiomyocytes subjected to high-glucose (HG) medium culture. Immunofluorescence study indicated that Mst1 overexpression enhanced, while Mst1 knockdown mitigated mitochondrial fission in DCM. Mst1 participated in the regulation of mitochondrial fission by upregulating the expression of Drp1, activating Drp1S616 phosphorylation and Drp1S637 dephosphorylation, as well as promoting Drp1 recruitment to the mitochondria. Furthermore, Drp1 knockdown abolished the effects of Mst1 on mitochondrial fission, mitochondrial membrane potential and mitochondrial dysfunction in cardiomyocytes subjected to HG treatment. These results indicated that Mst1 knockout inhibits mitochondrial fission and alleviates left ventricular remodeling thus prevents the development of DCM.

The Role of Mitochondrial Abnormalities in Diabetic Cardiomyopathy

“…Furthermore, Mst1 knockdown in diabetic mice inhibits mitochondrial fission and mitigates LV remodelling and cardiac dysfunction, thus preventing the DCM development. In addition, Drp1 knockdown prevents the effects of Mst1 on mitochondrial fission and DCM development, thus supporting the proposed Drp1-mediated mechanism [49].…”

Mitochondrial quality control in diabetic cardiomyopathy: from molecular mechanisms to therapeutic strategies

“…In diabetic hearts, Drp1 phosphorylation at Ser616 was induced, and this alteration was followed by cardiomyocyte hypertrophy and mitochondrial dysfunction, suggesting that post-translational modifications of mitochondrial dynamics proteins may contribute to mitochondrial dysfunction during DCM 111 . In the setting of DCM, other phosphorylated forms of Drp1 have also been detected, such as p-Drp1 Ser637 112 , p-Drp1 Ser579 113 and p-Drp1 Ser600 113 , 114 . Moreover, increased O-GlcNAcylation of Drp1 at threonine 585 and 586 was observed in diabetic heart mitochondria, correlating with elevated mitochondrial fragmentation in cardiomyocytes 115 .…”

Novel Insights Into the Pathogenesis of Diabetic Cardiomyopathy and Pharmacological Strategies

“…The role of Mst1 in the development of DCM is further corroborated in the Mst1 knockout mice. The deletion of Mst1 gene reduces mitochondrial fission and alleviates left ventricular remodeling and systolic dysfunction in diabetic mice ( 130 ). Most of the previous studies are conducted using STZ mice models.…”