Barth Syndrome: Exploring Cardiac Metabolism with Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract

Barth syndrome (BTHS) is an X-linked recessive multisystem disorder caused by mutations in the TAZ gene (TAZ, G 4.5, OMIM 300394) that encodes for the acyltransferase tafazzin. This protein is highly expressed in the heart and plays a significant role in cardiolipin biosynthesis. Heart disease is the major clinical manifestation of BTHS with a high incidence in early life. Although the genetic basis of BTHS and tetralinoleoyl cardiolipin deficiency in BTHS-affected individuals are well-established, downstream metabolic changes in cardiac metabolism are still uncovered. Our study aimed to characterize TAZ-induced metabolic perturbations in the heart. Control (PGP1-TAZWT) and TAZ mutant (PGP1-TAZ517delG) iPS-CM were incubated with 13C6-glucose and 13C5-glutamine and incorporation of 13C into downstream Krebs cycle intermediates was traced. Our data reveal that TAZ517delG induces accumulation of cellular long chain acylcarnitines and overexpression of fatty acid binding protein (FABP4). We also demonstrate that TAZ517delG induces metabolic alterations in pathways related to energy production as reflected by high glucose uptake, an increase in glycolytic lactate production and a decrease in palmitate uptake. Moreover, despite mitochondrial dysfunction, in the absence of glucose and fatty acids, TAZ517delG-iPS-CM can use glutamine as a carbon source to replenish the Krebs cycle.

Mitochondrial disease in children

“…However, it would be extremely challenging to prove that the extra X chromosome is indeed the cause of the differing phenotypes in these two siblings. Work on differentiated cells and organoids derived from induced pluripotent stem cells may eventually help to unravel the complex relationship between genotype and phenotype in mitochondrial diseases [141,142].…”

Modeling Cardiac Disease Mechanisms Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Progress, Promises and Challenges

“…Among cardiac diseases that are not recognized as channelopathies and/or structural cardiomyopathies, there are several metabolic disorders with cardiac phenotypes. Some of them, such as Friedreich’s ataxia [ 132 ], Barth syndrome [ 25 , 133 ], fatty acid oxidation disorders, and Pompe diseases [ 134 ] have successfully been translated to iPSC-CM-based models. Ion channelopathies are perhaps the form of cardiac disease with the most well-established iPSC-based disease models.…”

Metabolic Alterations Caused by Defective Cardiolipin Remodeling in Inherited Cardiomyopathies

“…A defect in PDH activity was not verified in an induced Pluripotent Stem Cell-derived Cardiomyocyte (iPSC-CM) model of BTHS, which even showed an increased flux of glucose into the Krebs cycle intermediate citrate. Accordingly, the anaplerotic supplementation by carboxylation of pyruvate was reduced in this cell model [ 88 ].…”

“…In addition, a CL-deficient yeast model showed alterations in the enzymatic activities of aconitase and succinate dehydrogenase [ 87 ]. Metabolic flux analyses in iPSC-CM displayed an increased level of the Krebs cycle intermediate citrates and decreased level of fumarate in BTHS, indicative of a reduced turnover of succinate into fumarate [ 88 ]. Aconitase and succinate dehydrogenase are strictly dependent on iron sulfur clusters as a cofactor.…”