Background Canonical studies indicate that cytochrome P450 2E1 ( CYP 2E1) plays a critical role in the metabolism of xenobiotics and ultimately participates in tissue damage. CYP 2E1 upregulates in the pathophysiological development of multiple diseases; however, the mechanism of CYP 2E1 upregulation, particularly in heart disease, remains elusive. Methods and Results We found that the level of CYP 2E1 increased in heart tissues from patients with hypertrophic cardiomyopathy; multiple mouse models of heart diseases, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and myocardial ischemia; and HL ‐1 myocytes under stress. We determined that Myc bound to the CYP 2E1 promoter and activated its transcription by bioinformatics analysis, luciferase activity, and chromatin immunoprecipitation, and Myc expression was modulated by extracellular signal–regulated kinases 1/2 and phosphatidylinositol 3 kinase/protein kinase B pathways under stress or injury in myocardium by signal transduction analysis. In addition, the level of oxidative stress and apoptosis gradually worsened with age in transgenic mice overexpressing CYP 2E1, which was significantly inhibited with CYP 2E1 knockdown. Conclusions Our results demonstrated that CYP 2E1 is likely a sensor of diverse pathophysiological factors and states in the myocardium. Upregulated CYP 2E1 has multiple pathophysiological roles in the heart, including increased oxidative stress and apoptosis as well as energy supply to meet the energy demand of the heart in certain disease states. Our discovery thus provides a basis for a therapeutic strategy for heart diseases targeting Myc and CYP 2E1.

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Background Iron‐sulfur cluster assembly 1 ( ISCA 1) is an iron‐sulfur (Fe/S) carrier protein that accepts Fe/S from a scaffold protein and transfers it to target proteins including the mitochondrial Fe/S containing proteins. ISCA 1 is also the newly identified causal gene for multiple mitochondrial dysfunctions syndrome ( MMDS ). However, our knowledge about the physiological function of ISCA 1 in vivo is currently limited. In this study, we generated an ISCA 1 knockout rat line and analyzed the embryo development. Methods ISCA 1 knockout rats were generated by replacing the exon1 of ISCA 1 gene with the mC herry‐Cre fusion gene using CRISPR ‐Cas9 technology. The ISCA 1 expression pattern was analyzed by fluorescence imaging using ISCA 1 promotor driven Cre and mC herry expression. The embryonic morphology was examinated by microscope and mitochondrial proteins were tested by Western blot. Results An ISCA 1 knockout rat line was obtained, which expressed mC herry‐Cre fusion protein. Both of the fluorescence images from mC herry and Cre induced mC herry in a reporter rat strain, showing that ISCA 1 expressed in most of the tissues in rats. The ISCA 1 knockout resulted in abnormal development at 8.5 days, with a significant decrease of NDUFA 9 protein and an increase of aconitase 2 ( ACO 2) in rat embryos. Conclusion Deletion of ISCA 1 induced early death in rats. ISCA 1 affected the expression of key proteins in the mitochondrial respiratory chain complex, suggesting that ISCA 1 has an important influence on the respiratory complex and energy metabolism.