2. Academic Validation
  3. Mitochondrial transplantation rescues Ca2+ homeostasis imbalance and myocardial hypertrophy in SLC25A3-related hypertrophic cardiomyopathy

Mitochondrial transplantation rescues Ca2+ homeostasis imbalance and myocardial hypertrophy in SLC25A3-related hypertrophic cardiomyopathy

  • Cell Rep. 2024 Dec 24;43(12):115065. doi: 10.1016/j.celrep.2024.115065.
Shuang Li 1,  Jianchao Zhang 2,  Wanrong Fu 2,  Jinhua Cao 2,  Zhonggen Li 2,  Xiaoxu Tian 2,  Meng Yang 3,  Jing Zhao 2,  Chuchu Wang 4,  Yangyang Liu 2,  Mengduan Liu 2,  Xiaoyan Zhao 2,  Xiaowei Li 5,  Jianzeng Dong 6,  Yuanming Qi 7
Affiliations

Affiliations

  • 1 School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China; Henan Key Laboratory of Hereditary Cardiovascular Diseases, Zhengzhou 450052, China.
  • 2 Henan Key Laboratory of Hereditary Cardiovascular Diseases, Zhengzhou 450052, China; Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
  • 3 Department of Cardiology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, China.
  • 4 School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 5 Henan Key Laboratory of Hereditary Cardiovascular Diseases, Zhengzhou 450052, China; Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address: fcclixw@zzu.edu.cn.
  • 6 Henan Key Laboratory of Hereditary Cardiovascular Diseases, Zhengzhou 450052, China; Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, National Clinical Research Centre for Cardiovascular Diseases, No. 2 Beijing Anzhen Road, Chaoyang District, Beijing 100029, China. Electronic address: jzdong@zzu.edu.cn.
  • 7 School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address: qym@zzu.edu.cn.
PMID: 39671292 DOI: 10.1016/j.celrep.2024.115065
Abstract

SLC25A3 encodes mitochondrial phosphate carrier (PiC), which is involved in inorganic phosphate transport. Clinical reports have found that most patients with homozygous or complex heterozygous mutations in SLC25A3 exhibit lactic acidosis, cardiac hypertrophy, and premature death. However, the potential molecular mechanisms underlying these associations remain unclear. Using CRISPR-Cas9 technology, we generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying SLC25A3-knockout (KO) or missense mutations (c.C544T, c.A547G, c.C349T) to elucidate the pathogenic mechanisms of SLC25A3-related hypertrophic cardiomyopathy (HCM) and evaluate potential therapeutic interventions. These SLC25A3-KO or missense mutation hiPSC-CMs recapitulated the disease phenotype associated with myocardial hypertrophy, including diastolic dysfunction, CA2+ homeostasis imbalance, and mitochondrial energy metabolism dysfunction. Further studies suggested the potential link between the accumulation of glycolytic byproducts and CA2+ homeostasis imbalance in SLC25A3-KO hiPSC-CMs. Finally, we explored the prospective therapeutic implications of mitochondrial transplantation in rescuing SLC25A3-related HCM.

Keywords

CP: Metabolism; Ca(2+) homeostasis imbalance; SLC25A3; glycolysis; mitochondrial transplantation; myocardial hypertrophy.

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