Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and apoptosis

Abstract

Aims/hypothesis Diabetic cardiomyopathy, characterised by increased oxidative damage and mitochondrial dysfunction, contributes to the increased risk of heart failure in individuals with diabetes. Considering that A-kinase anchoring protein 121 (AKAP1) is localised in the mitochondrial outer membrane and plays key roles in the regulation of mitochondrial function, this study aimed to investigate the role of AKAP1 in diabetic cardiomyopathy and explore its underlying mechanisms. Methods Loss-and gain-of-function approaches were used to investigate the role of AKAP1 in diabetic cardiomyopathy. Streptozotocin (STZ) was injected into Akap1-knockout (Akap1-KO) mice and their wild-type (WT) littermates to induce diabetes. In addition, primary neonatal cardiomyocytes treated with high glucose were used as a cell model of diabetes. Cardiac function was assessed with echocardiography. Akap1 overexpression was conducted by injecting adeno-associated virus 9 carrying Akap1 (AAV9-Akap1). LC-MS/MS analysis and functional experiments were used to explore underlying molecular mechanisms. Results AKAP1 was downregulated in the hearts of STZ-induced diabetic mouse models. Akap1-KO significantly aggravated cardiac dysfunction in the STZ-treated diabetic mice when compared with WT diabetic littermates, as evidenced by the left ventricular ejection fraction (LVEF; STZ-treated WT mice [WT/STZ] vs STZ-treated Akap1-KO mice [KO/STZ], 51.6% vs 41.6%). Mechanistically, Akap1 deficiency impaired mitochondrial respiratory function characterised by reduced ATP production. Additionally, Akap1 deficiency increased cardiomyocyte apoptosis via enhanced mitochondrial reactive oxygen species (ROS) production. Furthermore, immunoprecipitation and mass spectrometry analysis indicated that AKAP1 interacted with the NADH-ubiquinone oxidoreductase 75 kDa subunit (NDUFS1). Specifically, Akap1 deficiency inhibited complex I activity by preventing translocation of NDUFS1 from the cytosol to mitochondria. Akap1 deficiency was also related to decreased ATP production and enhanced mitochondrial ROS-related apoptosis. In contrast, restoration of AKAP1 expression in the hearts of STZ-treated diabetic mice promoted translocation of NDUFS1 to mitochondria and alleviated diabetic cardiomyopathy in the Bingchao Qi, Linjie He and Ya Zhao contributed equally to this work.

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