Depletion of cardiac cardiolipin synthase alters systolic and diastolic function

Elia Smeir; Sarah Leberer; Annelie Blumrich; Georg Vogler; Anastasia Vasiliades; Sandra Dresen; Carsten Jaeger; Yoann Gloaguen; Christian Klose; Dieter Beule; P Christian Schulze; Rolf Bodmer; Anna Foryst-Ludwig; Ulrich Kintscher

doi:10.1016/j.isci.2021.103314

Depletion of cardiac cardiolipin synthase alters systolic and diastolic function

iScience. 2021 Oct 19;24(11):103314. doi: 10.1016/j.isci.2021.103314. eCollection 2021 Nov 19.

Authors

Elia Smeir^{1

2}, Sarah Leberer^{1

2}, Annelie Blumrich^{1

2}, Georg Vogler³, Anastasia Vasiliades^{1

2}, Sandra Dresen^{1

2}, Carsten Jaeger⁴, Yoann Gloaguen^{5

6}, Christian Klose⁷, Dieter Beule⁵, P Christian Schulze⁸, Rolf Bodmer³, Anna Foryst-Ludwig^{1

2}, Ulrich Kintscher^{1

2}

Affiliations

¹ Charite - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health/ Institute of Pharmacology, Center for Cardiovascular Research, Hessische Street 3-4, 10115 Berlin, Germany.
² DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany.
³ Development, Aging and Regeneration Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
⁴ Federal Institute for Materials Research and Testing (BAM), Berlin, Germany.
⁵ Berlin Institute of Health, BIH, Core Unit Bioinformatics, Berlin, Germany.
⁶ Berlin Institute of Health, BIH, Metabolomics Platform, Berlin, Germany.
⁷ Lipotype GmbH, Dresden, Germany.
⁸ Department of Internal Medicine I, Division of Cardiology, Angiology, Pneumology and Intensive Medical Care, University Hospital Jena, Friedrich-Schiller-University Jena, Jena, Germany.

Abstract

Cardiolipin (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 in Drosophila melanogaster resulted 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.

Keywords: Animal physiology; Lipidomics; Molecular biology; Molecular physiology.

Abstract

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