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Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and apoptosis.
Diabetologia. 2020 05; 63(5):1072-1087.D

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 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.

Authors+Show Affiliations

Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, 710038, China.State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China. Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China.State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China. Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China. Laboratory Animal Center, Fourth Military Medical University, Xi'an, China.Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China.State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China. Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China.State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China. Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China.Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China.State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China. Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China.State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China. Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China.State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China. Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China.Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China. lifei2288@hotmail.com.Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, 710038, China. profleeyan@163.com.Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China. jilele@fmmu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32072193

Citation

Qi, Bingchao, et al. "Akap1 Deficiency Exacerbates Diabetic Cardiomyopathy in Mice By NDUFS1-mediated Mitochondrial Dysfunction and Apoptosis." Diabetologia, vol. 63, no. 5, 2020, pp. 1072-1087.
Qi B, He L, Zhao Y, et al. Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and apoptosis. Diabetologia. 2020;63(5):1072-1087.
Qi, B., He, L., Zhao, Y., Zhang, L., He, Y., Li, J., Li, C., Zhang, B., Huang, Q., Xing, J., Li, F., Li, Y., & Ji, L. (2020). Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and apoptosis. Diabetologia, 63(5), 1072-1087. https://doi.org/10.1007/s00125-020-05103-w
Qi B, et al. Akap1 Deficiency Exacerbates Diabetic Cardiomyopathy in Mice By NDUFS1-mediated Mitochondrial Dysfunction and Apoptosis. Diabetologia. 2020;63(5):1072-1087. PubMed PMID: 32072193.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and apoptosis. AU - Qi,Bingchao, AU - He,Linjie, AU - Zhao,Ya, AU - Zhang,Ling, AU - He,Yuanfang, AU - Li,Jun, AU - Li,Congye, AU - Zhang,Bo, AU - Huang,Qichao, AU - Xing,Jinliang, AU - Li,Fei, AU - Li,Yan, AU - Ji,Lele, Y1 - 2020/02/19/ PY - 2019/11/13/received PY - 2020/01/06/accepted PY - 2020/2/20/pubmed PY - 2021/6/1/medline PY - 2020/2/20/entrez KW - AKAP1 KW - Apoptosis KW - Diabetic cardiomyopathy KW - Mitochondrial dysfunction KW - NDUFS1 SP - 1072 EP - 1087 JF - Diabetologia JO - Diabetologia VL - 63 IS - 5 N2 - 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. SN - 1432-0428 UR - https://www.unboundmedicine.com/medline/citation/32072193/Akap1_deficiency_exacerbates_diabetic_cardiomyopathy_in_mice_by_NDUFS1_mediated_mitochondrial_dysfunction_and_apoptosis_ L2 - https://doi.org/10.1007/s00125-020-05103-w DB - PRIME DP - Unbound Medicine ER -