Cardiac Metabolic Pathways Affected in the Mouse Model of Barth Syndrome

Abstract

Cardiolipin (CL) is a mitochondrial phospholipid essential for electron transport chain (ETC) integrity. CL-deficiency in humans is caused by mutations in the tafazzin (Taz) gene and results in a multisystem pediatric disorder, Barth syndrome (BTHS). It has been reported that tafazzin deficiency destabilizes mitochondrial respiratory chain complexes and affects supercomplex assembly. The aim of this study was to investigate the impact of Taz-knockdown on the mitochondrial proteomic landscape and metabolic processes, such as stability of respiratory chain supercomplexes and their interactions with fatty acid oxidation enzymes in cardiac muscle. Proteomic analysis demonstrated reduction of several polypeptides of the mitochondrial respiratory chain, including Rieske and cytochrome c1 subunits of complex III, NADH dehydrogenase alpha subunit 5 of complex I and the catalytic core-forming subunit of F0F1-ATP synthase. Taz gene knockdown resulted in upregulation of enzymes of folate and amino acid metabolic pathways in heart mitochondria, demonstrating that Taz-deficiency causes substantive metabolic remodeling in cardiac muscle. Mitochondrial respiratory chain supercomplexes are destabilized in CL-depleted mitochondria from Taz knockdown hearts resulting in disruption of the interactions between ETC and the fatty acid oxidation enzymes, very long-chain acyl-CoA dehydrogenase and long-chain 3-hydroxyacyl-CoA dehydrogenase, potentially affecting the metabolic channeling of reducing equivalents between these two metabolic pathways. Mitochondria-bound myoglobin was significantly reduced in Taz-knockdown hearts, potentially disrupting intracellular oxygen delivery to the oxidative phosphorylation system. Our results identify the critical pathways affected by the Taz-deficiency in mitochondria and establish a future framework for development of therapeutic options for BTHS.

Barth Syndrome: Connecting Cardiolipin to Cardiomyopathy

“…BTHS mitochondria have reduced levels of super complexes and display decreased stability of existing super complexes [30,37]. In keeping with this, Huang et al [38] reported that ETC super complexes are destabilized in cardiolipin-depleted mitochondria from taz knockdown mouse hearts, an effect that potentially has an adverse affect on metabolic channeling of reducing equivalents. Likewise, Kiebish et al [39] reported that loss of tafazzin function in myocardium leads to changes in the mitochondrial lipidome, resulting in the dysregulated generation of oxidized derivatives of polyunsaturated fatty acids.…”

Biosynthesis, remodeling and turnover of mitochondrial cardiolipin

“…It has been established that CL deficiency can be responsible for the instability of cristae membrane supercomplexes [85]. Indeed, the abundance of such supercomplexes was found to be low in BTHS [45, 86, 87]. However, new data from our laboratory suggest that supercomplex instability may be the cause rather than the effect of CL deficiency in BTHS.…”

Pediatric Cardiomyopathies

“…Changes in cardiac proteome have been identified and measured in TAZ knockdown mouse models of human Barth syndrome. 175 The ability to generate induced pluripotent stem cell-cardiomyocyte models from individuals with Barth syndrome is an important development that may speed the assessment of potential therapies to correct the metabolic phenotype of the disease. 176 …”