Abstract 17903: Loss of Dihydrolipoamidsuccinyltransferase (DLST) Function Leads to Defective Energy Production and Impaired Cardiac Function
Mitochondriopathies in humans lead to myopathies, arrhythmias and affect the central nervous system. However, due to early lethality and only few reported cases, the detailed role during heart development and the impact on cardiac function is still unknown.
By a forward genetics approach in zebrafish, we isolated the mutant line Schneckentempo (ste) and were able to demonstrate the pivotal role of regular mitochondrial function for the development and function of heart and muscle. Already at early developmental stages ste mutants exhibit impaired cardiac function accompanied by significantly reduced heart rates as well as morphological alterations of the skeletal muscle leading to decreased motility. By positional cloning and gene knock down analyses by Morpholino-modified antisense oligonucleotides we determined a loss of function mutation of the dihydrolipoamidsuccinyltransferase (DLST) gene to cause the ste phenotype. The enzyme DLST is part of the α ketoglutarate dehydrogenase complex of the citric acid cycle localized in mitochondria which are involved in energy production to provide the main energy equivalent ATP. We show that in ste mutant embryos the ATP content is significantly reduced, suggesting that limited energy supply is the molecular cause for the observed cardiac phenotype in ste mutants. To validate these findings, we performed targeted knock-downs of oxoglutaratdehydrogenase (OGDH) and dihydrolipoamid dehydrogenase (DLDH), two other essential components of the α ketoglutarate dehydrogenase complex. Intriguingly, we find that the knock-down of each enzyme of the α -ketoglutarate dehydrogenase complex as well as the pharmacological blockade of the citric acid cycle is accompanied by significantly reduced ATP production and the development of severe bradycardia in these embryos. Therefore, we show for the first time, that loss of DLST leads to impaired cardiac function in vivo due to defective energy production.
- © 2013 by American Heart Association, Inc.