1. Academic Validation
  2. Delivery of mitochondria confers cardioprotection through mitochondria replenishment and metabolic compliance

Delivery of mitochondria confers cardioprotection through mitochondria replenishment and metabolic compliance

  • Mol Ther. 2023 Feb 18;S1525-0016(23)00079-5. doi: 10.1016/j.ymthe.2023.02.016.
Alian Zhang 1 Yangyang Liu 1 Jianan Pan 2 Francesca Pontanari 3 Andrew Chia-Hao Chang 3 Honghui Wang 3 Shuang Gao 4 Changqian Wang 2 Alex Cy Chang 5
Affiliations

Affiliations

  • 1 Department of Cardiology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.
  • 2 Department of Cardiology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
  • 3 Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.
  • 4 Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China; Department of Clinical Medicine, Jining Medical University, Jining 272000, China.
  • 5 Department of Cardiology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China. Electronic address: alexchang@shsmu.edu.cn.
Abstract

Mitochondrial dysfunction is a hallmark of heart failure. Mitochondrial transplantation has been demonstrated to be able to restore heart function but its mechanism of action remains unresolved. Using an in-house optimized Mitochondrial Isolation method, we tested efficacy of mitochondria transplantation in two different heart failure models. First using the doxorubicin-induced heart failure model, we demonstrate that mitochondrial transplantation prior to doxorubicin challenge protects cardiac function in vivo, prevents myocardial Apoptosis, but contraction improvement relies on the metabolic compatibility between transplanted mitochondria and treated cardiomyocytes. Second, using mutation driven dilated cardiomyopathic human induced pluripotent stem cell-derived cardiomyocyte model, we demonstrate that mitochondrial transplantation preferentially boosts contraction in ventricular myocytes. Last, using single cell RNASeq, we show that mitochondria transplantation boosts contractility in dystrophic cardiomyocytes with little transcriptomic alterations. Together, we provide evidence that mitochondria transplantation confers myocardial protection and may serve as a potential therapeutic option for heart failure.

Keywords

dilated cardiomyopathy; doxorubicin; iPSC; mitochondria delivery.

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