Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure, and thousands of mutations that cause cardiomyopathy have been characterized within more than 100 genes to date. Understanding the genetic basis of DCM facilitates disease diagnosis and treatment, and it also uncovers the essential genes involved in maintaining normal cardiac physiology, bring us closer to our long-term goal of identifying new therapeutic targets of human cardiomyopathy.GATA zinc finger domain containing 1 (GATAD1) has been identified in patient cohorts with autosomal recessive dilated cardiomyopathy. However, the specific role of GATAD1 in cardiomyocyte, and the molecular mechanisms by which GATAD1 loss of function results in cardiomyopathy remains unknown. To determine the molecular basis underlying the cardiomyopathy caused by the GATAD1 deficiency, we generated a Gatad1 cardiomyocyte (CM)-specific knockout (cKO) mice. We performed physiological, histological, and biochemical analyses of Gatad1 cKO mice to determine the functional, morphological, and molecular consequences of its autosomal recessive mutation. We found that Gatad1 cKO mice displayed normal cardiac function and morphology up to 18 months of age, although increased in the expression levels of the cardiac stress markers were observed at both 3 months and 15 months stage. We also observed that cardiomyocytes isolated from Gatad1 cKO mice displayed normal nuclear shape, compared to the controls. Under pressure overload, the Gatad1 cKO mice also exhibit similar hypertrophic response, compared to controls. In conclusion, our data suggest that the deletion of Gatad1 does not cause cardiomyopathy at basal condition or in response to pressure overload stress in mice.

Mitochondrial dysfunction in heart triggers an integrated stress response (ISR) through phosphorylation of eIF2α and subsequent ATF4 activation. DAP3 Binding Cell Death Enhancer 1 (DELE1) is a mitochondrial protein recently found to be critical for mediating mitochondrial stress-triggered ISR (MSR)-induced eIF2α-ATF4 pathway activation. However, the specific role of DELE1 in heart at baseline or in response to mitochondrial stress and acquired cardiomyopathy remains largely unknown. In this study, we report that DELE1 is dispensable for cardiac development and function under baseline conditions. Conversely, DELE1 is essential for mediating an adaptive response to mitochondrial dysfunction-triggered stress in the heart, playing a protective role in mitochondrial cardiomyopathy. We also found that DELE1 cKO mice exhibit similar cardiac structure and function, compared with controls, in response to pressure overload-induced heart failure.