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Barth Syndrome: Connecting Cardiolipin to Cardiomyopathy

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Lipids

Abstract

The Barth syndrome (BTHS) is caused by an inborn error of metabolism that manifests characteristic phenotypic features including altered mitochondrial membrane phospholipids, lactic acidosis, organic acid-uria, skeletal muscle weakness and cardiomyopathy. The underlying cause of BTHS has been definitively traced to mutations in the tafazzin (TAZ) gene locus on chromosome X. TAZ encodes a phospholipid transacylase that promotes cardiolipin acyl chain remodeling. Absence of tafazzin activity results in cardiolipin molecular species heterogeneity, increased levels of monolysocardiolipin and lower cardiolipin abundance. In skeletal muscle and cardiac tissue mitochondria these alterations in cardiolipin perturb the inner membrane, compromising electron transport chain function and aerobic respiration. Decreased electron flow from fuel metabolism via NADH ubiquinone oxidoreductase activity leads to a buildup of NADH in the matrix space and product inhibition of key TCA cycle enzymes. As TCA cycle activity slows pyruvate generated by glycolysis is diverted to lactic acid. In turn, Cori cycle activity increases to supply muscle with glucose for continued ATP production. Acetyl CoA that is unable to enter the TCA cycle is diverted to organic acid waste products that are excreted in urine. Overall, reduced ATP production efficiency in BTHS is exacerbated under conditions of increased energy demand. Prolonged deficiency in ATP production capacity underlies cell and tissue pathology that ultimately is manifest as dilated cardiomyopathy.

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Abbreviations

TAZ :

The tafazzin gene

BTHS:

Barth syndrome

IMM:

Inner mitochondrial membrane

ETC:

Electron transport chain

ER:

Endoplasmic reticulum

ALCAT1:

Acyl CoA lysocardiolipin acyltransferase

MLCAT:

Monolysocardiolipin acyltransferase

HMG CoA:

3-Hydroxy 3-methylglutaryl CoA

3MG CoA:

3-Methylglutaconyl CoA

3MGA:

3-Methylglutaconic acid

2-EHA:

2-Ethylhydracrylic acid

LVNC:

Left ventricular non-compaction

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Acknowledgements

This work was supported by a grant from the US National Institutes of Health (R37 HL64159). NI was supported by NIH training Grant T32 DK061918.

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  1. Children’s Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA, 94609, USA

    Nikita Ikon & Robert O. Ryan

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  1. Nikita Ikon
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Correspondence to Robert O. Ryan.

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Nikita Ikon and Robert O. Ryan declare that they have no conflict of interest.

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Ikon, N., Ryan, R.O. Barth Syndrome: Connecting Cardiolipin to Cardiomyopathy. Lipids 52, 99–108 (2017). https://doi.org/10.1007/s11745-016-4229-7

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