Theranostics 2019; 9(13):3687-3706. doi:10.7150/thno.33684 This issue Cite

Research Paper

Targeting mitochondrial dynamics by regulating Mfn2 for therapeutic intervention in diabetic cardiomyopathy

Lang Hu1*, Mingge Ding2*, Daishi Tang3*, Erhe Gao4, Congye Li1, Kaiyan Wang5, Bingchao Qi1, Jihuan Qiu1, Huishou Zhao1, Pan Chang6, Feng Fu5✉, Yan Li1✉

1. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
2. Department of Cardiology, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an, 710003, China
3. Department of Endocrinology, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116000, China
4. Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
5. Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, 710032, China
6. Department of Cardiology, The Second Affiliated Hospital of Xi'an Medical University, Xi'an 710038, China.
*These authors contributed equally to this work.

Citation:
Hu L, Ding M, Tang D, Gao E, Li C, Wang K, Qi B, Qiu J, Zhao H, Chang P, Fu F, Li Y. Targeting mitochondrial dynamics by regulating Mfn2 for therapeutic intervention in diabetic cardiomyopathy. Theranostics 2019; 9(13):3687-3706. doi:10.7150/thno.33684. https://www.thno.org/v09p3687.htm
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Abstract

Graphic abstract

Increasing evidence has implicated the important role of mitochondrial pathology in diabetic cardiomyopathy (DCM), while the underlying mechanism remains largely unclear. The aim of this study was to investigate the role of mitochondrial dynamics in the pathogenesis of DCM and its underlying mechanisms.

Methods: Obese diabetic (db/db) and lean control (db/+) mice were used in this study. Mitochondrial dynamics were analyzed by transmission electron microscopy in vivo and by confocal microscopy in vitro.

Results: Diabetic hearts from 12-week-old db/db mice showed excessive mitochondrial fission and significant reduced expression of Mfn2, while there was no significant alteration or slight change in the expression of other dynamic-related proteins. Reconstitution of Mfn2 in diabetic hearts inhibited mitochondrial fission and prevented the progression of DCM. In an in-vitro study, cardiomyocytes cultured in high-glucose and high-fat (HG/HF) medium showed excessive mitochondrial fission and decreased Mfn2 expression. Reconstitution of Mfn2 restored mitochondrial membrane potential, suppressed mitochondrial oxidative stress and improved mitochondrial function in HG/HF-treated cardiomyocytes through promoting mitochondrial fusion. In addition, the down-regulation of Mfn2 expression in HG/HF-treated cardiomyocytes was induced by reduced expression of PPARα, which positively regulated the expression of Mfn2 by directly binding to its promoter.

Conclusion: Our study provides the first evidence that imbalanced mitochondrial dynamics induced by down-regulated Mfn2 contributes to the development of DCM. Targeting mitochondrial dynamics by regulating Mfn2 might be a potential therapeutic strategy for DCM.

Keywords: Diabetic cardiomyopathy, Mitochondrial dynamics, Mitochondrial dysfunction, Mfn2, PPARα


Citation styles

APA
Hu, L., Ding, M., Tang, D., Gao, E., Li, C., Wang, K., Qi, B., Qiu, J., Zhao, H., Chang, P., Fu, F., Li, Y. (2019). Targeting mitochondrial dynamics by regulating Mfn2 for therapeutic intervention in diabetic cardiomyopathy. Theranostics, 9(13), 3687-3706. https://doi.org/10.7150/thno.33684.

ACS
Hu, L.; Ding, M.; Tang, D.; Gao, E.; Li, C.; Wang, K.; Qi, B.; Qiu, J.; Zhao, H.; Chang, P.; Fu, F.; Li, Y. Targeting mitochondrial dynamics by regulating Mfn2 for therapeutic intervention in diabetic cardiomyopathy. Theranostics 2019, 9 (13), 3687-3706. DOI: 10.7150/thno.33684.

NLM
Hu L, Ding M, Tang D, Gao E, Li C, Wang K, Qi B, Qiu J, Zhao H, Chang P, Fu F, Li Y. Targeting mitochondrial dynamics by regulating Mfn2 for therapeutic intervention in diabetic cardiomyopathy. Theranostics 2019; 9(13):3687-3706. doi:10.7150/thno.33684. https://www.thno.org/v09p3687.htm

CSE
Hu L, Ding M, Tang D, Gao E, Li C, Wang K, Qi B, Qiu J, Zhao H, Chang P, Fu F, Li Y. 2019. Targeting mitochondrial dynamics by regulating Mfn2 for therapeutic intervention in diabetic cardiomyopathy. Theranostics. 9(13):3687-3706.

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