Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9

Metabolic Adaptations to Dysfunctional Mitochondria in Barth Syndrome Cardiomyopathy
C. Wasmus1, I. Kutschka1, E. Bertero1, M. Erk1, B. Arslan1, W. Schmitz2, P. Rehling3, K. Guan4, T. Higuchi1, C. Maack1, J. Dudek1, für die Studiengruppe: DZHI
1Deutsches Zentrum für Herzinsuffizienz, Universitätsklinikum Würzburg, Würzburg; 2Lehrstuhl für Biochemie und Molekularbiologie, Universität Würzburg, Würzburg; 3Institut für Zellbiochemie, Universitätsmedizin Göttingen, Göttingen; 4Institut für Pharmakologie und Toxikologie, Medizinische Fakultät Carl Gustav Carus der TU Dresden, Dresden;

Barth syndrome (BTHS) is a rare disease caused by an inherited dysfunction in mitochondria. Mitochondria in the heart play a pivotal role in providing 95% of the cardiac energy demand. BTHS patients suffer from cardiomyopathy, immune deficiency, growth retardation and skeletal myopathy. Our previous work has shown that in BTHS, a defect in the enzyme tafazzin, involved in the remodeling of the mitochondrial phospholipid cardiolipin (CL) imposes a defect in the respiratory chain, in the Krebs cycle and in mitochondrial Ca2+ homeostasis. Collectively, these defects affect energy production and redox homeostasis. Here, we elucidate how mitochondrial dysfunction causes a defect in the metabolism of fatty acids, the most prominent energy substrate of the heart. Using an inducible tafazzin knock-down mouse model and patient derived iPS-cardiomyocytes, we find that mitochondrial dysfunction in BTHS not only impairs β-oxidation, but also fatty acid transport into mitochondria. The transport of fatty acids across the inner mitochondrial membrane follows after their reversible transacylation with carnitine. We reveal alterations in the gene and protein expression of enzymes involved in the carnitine-shuttle system in BTHS. PET-CT tracer experiments displayed a decrease in mitochondrial fatty acid metabolism and a compensatory rewiring of cardiac metabolism. We reveal that metabolic remodeling in BTHS induces increased oxidation of amino acids as an alternative energy source in BTHS. This unique metabolic rerouting of energy flux allows for novel therapeutic strategies to support mitochondrial energy production and redox homeostasis. Therapeutic concepts to either promote fatty acid metabolism and/or supplementing amino acid metabolism are tested here and provide promising insights into future concepts of therapeutic interventions.