摘要：SummaryCardiolipin (CL) is a major cardiac mitochondrial phospholipid maintaining regular mitochondrial morphology and function in cardiomyocytes. Cardiac CL production includes its biosynthesis and a CL remodeling process. Here we studied the impact of CL biosynthesis and the enzyme cardiolipin synthase (CLS) on cardiac function. CLS and cardiac CL species were significantly downregulated in cardiomyocytes following catecholamine-induced cardiac damage in mice, accompanied by increased oxygen consumption rates, signs of oxidative stress, and mitochondrial uncoupling. RNAi-mediated cardiomyocyte-specific knockdown of CLS inDrosophila melanogasterresulted in marked cardiac dilatation, severe impairment of systolic performance, and slower diastolic filling velocity assessed by fluorescence-based heart imaging. Finally, we showed that CL72:8 is significantly decreased in cardiac samples from patients with heart failure with reduced ejection fraction (HFrEF). In summary, we identified CLS as a regulator of cardiac function. Considering the cardiac depletion of CL species in HFrEF, pharmacological targeting of CLS may be a promising therapeutic approach.Graphical abstractDisplay OmittedHighlights•Cardiolipin synthase (CLS) is reduced in isoproterenol (ISO)-induced cardiac damage•This is accompanied by alterations of cardiolipins and mitochondrial function•CLS mutantDrosophila melanogasterexhibit mild cardiac changes•Cardiomyocyte-CLS knockdown inDrosophilaresults in severe cardiac dysfunctionAnimal physiology; Molecular physiology; Molecular biology; Lipidomics
