title: Loss of dihydrolipoyl succinyltransferase (DLST) leads to reduced resting heart rate in the zebrafish.
abstract: The genetic underpinnings of heart rate regulation are only poorly understood. In search for genetic regulators of cardiac pacemaker activity, we isolated in a large-scale mutagenesis screen the embryonic lethal, recessive zebrafish mutant schneckentempo (ste). Homozygous ste mutants exhibit a severely reduced resting heart rate with normal atrio-ventricular conduction and contractile function. External electrical pacing reveals that defective excitation generation in cardiac pacemaker cells underlies bradycardia in ste (-/-) mutants. By positional cloning and gene knock-down analysis we find that loss of dihydrolipoyl succinyltransferase (DLST) function causes the ste phenotype. The mitochondrial enzyme DLST is an essential player in the citric acid cycle that warrants proper adenosine-tri-phosphate (ATP) production. Accordingly, ATP levels are significantly diminished in ste (-/-) mutant embryos, suggesting that limited energy supply accounts for reduced cardiac pacemaker activity in ste (-/-) mutants. We demonstrate here for the first time that the mitochondrial enzyme DLST plays an essential role in the modulation of the vertebrate heart rate by controlling ATP production in the heart.
authors.affiliation: Department of Medicine II, Cardiology, University of Ulm Medical Center, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Keßler
authors.forename: Ina M
authors.initials: IM
authors.lastname: Berger
authors.forename: Steffen
authors.initials: S
authors.lastname: Just
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rottbauer
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D055785:Gene Knockdown Techniques; D006339:Heart Rate / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D015027:Zebrafish
chemical_list: D000217:Acyltransferases; C021515:dihydrolipoamide succinyltransferase