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.
Highlights
Barth syndrome (BTHS) is an X-linked recessive multisystem disorder associated with cardiomyopathy, neutropenia, exercise intolerance, sudden cardiac death, skeletal muscle weakness, recurrent bacterial infections and growth delay [1,2]
The most significant portion of adenosine 5- triphosphate (ATP) synthesis in heart is driven by fatty acids catabolism; in response to developing pathologies, cardiomyocytes can shift their reliance from fatty acids to other carbon sources
To determine the effect of TAZ 517delG on carbon source selection, control and TAZ517delG - iPS-CMs were incubated first with 10 mM 13 C6 -glucose and 0.4 mM unlabeled palmitate (BSA conjugated) and in a separate experiment cells were incubated with 10 mM unlabeled glucose with 0.4 mM 13 C16 -palmitate (BSA-conjugated)
Summary
Barth syndrome (BTHS) is an X-linked recessive multisystem disorder associated with cardiomyopathy, neutropenia, exercise intolerance, sudden cardiac death, skeletal muscle weakness, recurrent bacterial infections and growth delay [1,2]. Cardiomyocytes derived from iPSCs recapitulate the donor genotype, reproducing the complex metabolic conditions of the affected individual’s heart and exhibit many of the characteristics of in vivo cardiomyocytes [18,19] including syncytial and contractile activities, ion channels, receptors, and transporters. These characteristics make iPS-CMs a good alternative model to delineate cellular mechanisms underlying BTHS cardiac phenotype. Our study aimed to investigate the metabolic consequences of a TAZ517delG mutation in an iPS-CM model of Barth syndrome This was achieved by experimental workflows with stable isotope-labeled tracers, targeted metabolic profiling and targeted gene expression.
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