Background:

Cardiac remodeling is the initiating factor in the development of heart failure(HF), which can occur in various cardiomyopathies. cytochrome c oxidase subunit 6A2(COX6A2) is one of the components of cytochrome c oxidase, which drives oxidative phosphorylation. The pathogenesis of myocardial remodeling caused by COX6A2 deficiency in humans remains unclear due to the lack of a suitable research model. In this study, we established a COX6A2-deficient human cardiac myocyte(CM) model mimicking "human COX6A2 homozygous mutation" to explore the potential effects of COX6A2 dysfunction and its mechanism of action.

Methods:

: Human COX6A2 homozygous knockout cardiomyocytes model was established by combining CRISPR/Cas9 gene editing technology and hiPSCs directed differentiation technology. Cell model phenotypic assays were then performed to characterize the pathological features of COX6A2-deficient cardiomyocytes.

Results:

: COX6A2 gene knockout did not affect the pluripotency and differentiation efficiency of hiPSCs. Myocardial cells with COX6A2 gene knockout showed abnormal energy metabolism, increased oxidative stress level, abnormal calcium transport and decreased contractility. In addition, L-carnitine and trimetazidine significantly improved energy metabolism in COX6A2 deficient human myocardial model.

Conclusions:

: We have established a COX6A2-deficient human cardiomyocyte model that exhibits abnormal energy metabolism, elevated oxidative stress levels, abnormal calcium transport, and reduced contractility. This model is an important tool to help understand the mechanism of action of energy metabolism disorders leading to myocardial remodeling, elucidate the gene-phenotype relationship of COX6A2 deficiency, and facilitate drug screening.