Mitochondrial transplantation ameliorates doxorubicin-induced cardiac dysfunction via activating glutamine metabolism

Xiaolei Sun; Hang Chen; Rifeng Gao; Ya Huang; Yanan Qu; Heng Yang; Xiang Wei; Shiyu Hu; Jian Zhang; Peng Wang; Yunzeng Zou; Kai Hu; Junbo Ge; Aijun Sun

doi:10.1016/j.isci.2023.107790

Mitochondrial transplantation ameliorates doxorubicin-induced cardiac dysfunction via activating glutamine metabolism

iScience. 2023 Sep 1;26(10):107790. doi: 10.1016/j.isci.2023.107790. eCollection 2023 Oct 20.

Authors

Xiaolei Sun^{1

2

3

4}, Hang Chen^{1

2

3

4

5}, Rifeng Gao⁶, Ya Huang^{1

2

3

4}, Yanan Qu^{1

2

3

4}, Heng Yang⁷, Xiang Wei⁶, Shiyu Hu^{1

2

3

4}, Jian Zhang^{1

2

3

4}, Peng Wang^{1

2

3

4}, Yunzeng Zou^{1

2

3

4

8}, Kai Hu^{1

2

3

4}, Junbo Ge^{1

2

3

4

8}, Aijun Sun^{1

2

3

4

8}

Affiliations

¹ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
² Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, P.R. China.
³ NHC Key Laboratory of Viral Heart Diseases, Shanghai 200032, P.R. China.
⁴ Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai 200032, P.R. China.
⁵ Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, P.R. China.
⁶ Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, P.R. China.
⁷ The Second Affiliated Hospital of Nanchang University, Nanchang 330000, P.R. China.
⁸ Institute of Biomedical Science, Fudan University, Shanghai 200032, P.R. China.

Abstract

Doxorubicin is a wildly used effective anticancer agent. However, doxorubicin use is also related to cardiotoxic side effect in some patients. Mitochondrial damage has been shown to be one of the pathogeneses of doxorubicin-induced myocardial injury. In this study, we demonstrated that mitochondrial transplantation could inhibit doxorubicin-induced cardiotoxicity by directly supplying functional mitochondria. Mitochondrial transplantation improved contractile function and respiratory capacity, reduced cellular apoptosis and oxidative stress in cardiomyocytes. Mitochondria isolated from various sources, including mouse hearts, mouse and human arterial blood, and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), all exerted similar cardioprotective effects. Mechanically, mitochondrial transplantation activates glutamine metabolism in doxorubicin-treated mice heart and blocking glutamine metabolism attenuated the cardioprotective effects of mitochondrial transplantation. Overall, our study demonstrates that mitochondria isolated from arterial blood could be used for mitochondrial transplantation, which might serve as a feasible promising therapeutic option for patients with doxorubicin-induced cardiotoxicity.

Keywords: Biochemistry; Cell biology; Cellular physiology; Metabolomics; Molecular physiology.