Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and
Bingchao Qi1, Linjie He2,3, Ya Zhao2,3,4
1Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, 710038, China.
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 LVEF (WT/STZ injected with adeno-associated virus carrying gfp [AAV9-gfp] vs WT/STZ AAV9-Akap1, 52.4% vs 59.6%; KO/STZ AAV9-gfp vs KO/STZ AAV9-Akap1, 42.2% vs 57.6%).
Conclusions/Interpretation:
Our study provides the first evidence that Akap1 deficiency exacerbates diabetic cardiomyopathy by impeding mitochondrial translocation of NDUFS1 to induce mitochondrial dysfunction and cardiomyocyte apoptosis. Our findings suggest that Akap1 upregulation has therapeutic potential for myocardial injury in individuals with diabetes.
Insights
A-kinase anchoring protein 121 (AKAP1) deficiency worsens diabetic cardiomyopathy by impairing mitochondrial function and increasing cell death. Upregulating AKAP1 may offer a therapeutic strategy for diabetic heart injury.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Diabetes Research
Background:
- Diabetic cardiomyopathy increases heart failure risk due to oxidative damage and mitochondrial dysfunction.
- A-kinase anchoring protein 121 (AKAP1) is crucial for mitochondrial function, located in the mitochondrial outer membrane.
Purpose of the Study:
- To investigate the role of AKAP1 in diabetic cardiomyopathy.
- To explore the underlying molecular mechanisms of AKAP1's involvement.
Main Methods:
- Utilized Akap1-knockout (Akap1-KO) and wild-type (WT) mice treated with streptozotocin (STZ) to model diabetes.
- Employed primary neonatal cardiomyocytes under high glucose conditions as a cellular model.
- Assessed cardiac function via echocardiography and explored molecular mechanisms using LC-MS/MS and immunoprecipitation.
Main Results:
- AKAP1 was downregulated in diabetic hearts; Akap1 deficiency exacerbated cardiac dysfunction and reduced left ventricular ejection fraction (LVEF).
- Akap1 deficiency impaired mitochondrial respiration, reduced ATP production, and increased cardiomyocyte apoptosis via reactive oxygen species (ROS).
- AKAP1 interacts with NDUFS1, and its deficiency prevents NDUFS1 translocation, inhibiting Complex I activity.
Conclusions:
- Akap1 deficiency exacerbates diabetic cardiomyopathy by hindering NDUFS1 mitochondrial translocation, leading to mitochondrial dysfunction and apoptosis.
- Upregulation of AKAP1 demonstrates therapeutic potential for mitigating myocardial injury in diabetes.
