Mfn2-mediated mitochondrial fusion alleviates doxorubicin-induced cardiotoxicity with enhancing its anticancer activity through metabolic switch
Mingge Ding,
Rui Shi,
Shuli Cheng,
Man Li,
Dema De,
Chaoyang Liu,
Xiaoming Gu,
Juan Li,
Shumiao Zhang,
Min Jia,
Rong Fan,
Jianming Pei,
Feng Fu
Affiliations
Mingge Ding
Department of Geriatrics Cardiology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China; Corresponding author. Department of Geriatrics Cardiology, The Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, China.
Rui Shi
Department of Geriatrics Cardiology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China; Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, China
Shuli Cheng
Dentofacial Development Management Center, Hospital of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China
Man Li
Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, China; School of Life Science, Northwest University, Xi'an, Shaanxi, 710069, China
Dema De
Department of Geriatrics Cardiology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China; Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, China
Chaoyang Liu
Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, China
Xiaoming Gu
Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, China
Juan Li
Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, China
Shumiao Zhang
Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, China
Min Jia
Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, China
Rong Fan
Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, China
Jianming Pei
Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, China; Corresponding author. Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, China.
Feng Fu
Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, China; Corresponding author. Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, China.
Imbalanced mitochondrial dynamics including inhibited mitochondrial fusion is associated with cardiac dysfunction as well as tumorigenesis. This study sought to explore the effects of promoting mitochondrial fusion on doxorubicin(Dox)-induced cardiotoxicity and its antitumor efficacy, with a focus on the underlying metabolic mechanisms. Herein, the inhibition of Mfn2-mediated mitochondrial fusion was identified as a key phenotype in Dox-induced cardiotoxicity. Restoration of Mfn2-mediated mitochondrial fusion enhanced mitochondrial oxidative metabolism, reduced cellular injury/apoptosis and inhibited mitochondria-derived oxidative stress in the Dox-treated cardiomyocytes. Application of lentivirus expressing Drp1 (mitochondrial fusion inhibitor) or Rote/Anti A (mitochondrial complex I/III inhibitors) blunted the above protective effects of Mfn2. Cardiac-specific Mfn2 transgenic mice showed preserved mitochondrial fusion and attenuated myocardial injury upon Dox exposure in vivo. The suppression of Mfn2-mediated mitochondrial fusion was induced by Dox-elicited upregulation of FoxO1, which inhibited the transcription of Mfn2 by binding to its promoter sites. In the B16 melanoma, Mfn2 upregulation not only attenuated tumor growth alone but also further delayed tumor growth in the presence of Dox. Mechanistically, Mfn2 synergized with the inhibitory action of Dox on glycolysis metabolism in the tumor cells. One common feature in both cardiomyocytes and tumor cells was that Mfn2 increased the ratio of oxygen consumption rate to extracellular acidification rate, suggesting Mfn2 triggered a shift from aerobic glycolysis to mitochondrial oxidative metabolism. In conclusion, targeting Mfn2-mediated mitochondrial fusion may provide a dual therapeutic advantage in Dox-based chemotherapy by simultaneously defending against Dox-induced cardiotoxicity and boosting its antitumor potency via metabolic shift.
