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

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, Ca