Barth Syndrome: Connecting Cardiolipin to Cardiomyopathy
- PMID: 28070695
- PMCID: PMC5288132
- DOI: 10.1007/s11745-016-4229-7
Barth Syndrome: Connecting Cardiolipin to Cardiomyopathy
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.
Keywords: 3-Methylglutaconic acid; Barth syndrome; Cardiolipin; Cori cycle; Dilated cardiomyopathy; Electron transport chain; Inner mitochondrial membrane; Lactic acid; NADH oxidation; Organic aciduria; Tafazzin.
Conflict of interest statement
Nikita Ikon and Robert O. Ryan declare that they have no conflict of interest.
Figures
![Figure 1](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5288132/bin/nihms842227f1.gif)
![Figure 2](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5288132/bin/nihms842227f2.gif)
![Figure 3](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5288132/bin/nihms842227f3.gif)
![Figure 4](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5288132/bin/nihms842227f4.gif)
![Figure 5](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/5288132/bin/nihms842227f5.gif)
Similar articles
-
Tafazzin deficiency impairs CoA-dependent oxidative metabolism in cardiac mitochondria.J Biol Chem. 2020 Aug 28;295(35):12485-12497. doi: 10.1074/jbc.RA119.011229. Epub 2020 Jul 14. J Biol Chem. 2020. PMID: 32665401 Free PMC article.
-
Long-chain fatty acid oxidation and respiratory complex I deficiencies distinguish Barth Syndrome from idiopathic pediatric cardiomyopathy.J Inherit Metab Dis. 2022 Jan;45(1):111-124. doi: 10.1002/jimd.12459. Epub 2021 Dec 7. J Inherit Metab Dis. 2022. PMID: 34821394
-
Barth syndrome: cellular compensation of mitochondrial dysfunction and apoptosis inhibition due to changes in cardiolipin remodeling linked to tafazzin (TAZ) gene mutation.Biochim Biophys Acta. 2013 Aug;1832(8):1194-206. doi: 10.1016/j.bbadis.2013.03.005. Epub 2013 Mar 20. Biochim Biophys Acta. 2013. PMID: 23523468
-
Cardiolipin metabolism and its causal role in the etiology of the inherited cardiomyopathy Barth syndrome.Chem Phys Lipids. 2015 Dec;193:1-10. doi: 10.1016/j.chemphyslip.2015.09.005. Epub 2015 Sep 26. Chem Phys Lipids. 2015. PMID: 26415690 Review.
-
Experimental models of Barth syndrome.J Inherit Metab Dis. 2022 Jan;45(1):72-81. doi: 10.1002/jimd.12423. Epub 2021 Aug 15. J Inherit Metab Dis. 2022. PMID: 34370877 Free PMC article. Review.
Cited by
-
Epstein-Barr-Virus-Driven Cardiolipin Synthesis Sustains Metabolic Remodeling During B-cell Lymphomagenesis.Res Sq [Preprint]. 2024 Apr 8:rs.3.rs-4013392. doi: 10.21203/rs.3.rs-4013392/v1. Res Sq. 2024. PMID: 38659762 Free PMC article. Preprint.
-
Why Don't More Mitochondrial Diseases Exhibit Cardiomyopathy?J Cardiovasc Dev Dis. 2023 Apr 1;10(4):154. doi: 10.3390/jcdd10040154. J Cardiovasc Dev Dis. 2023. PMID: 37103033 Free PMC article.
-
Sex-Specific Patterns of Diaphragm Phospholipid Content and Remodeling during Aging and in a Model of SELENON-Related Myopathy.Biomedicines. 2023 Jan 17;11(2):234. doi: 10.3390/biomedicines11020234. Biomedicines. 2023. PMID: 36830771 Free PMC article.
-
Prenatal case report of Barth syndrome caused by novel TAFAZZIN mutation: Clinical characteristics of fetal dilated cardiomyopathy with ascites.Front Pediatr. 2022 Nov 9;10:1004485. doi: 10.3389/fped.2022.1004485. eCollection 2022. Front Pediatr. 2022. PMID: 36440345 Free PMC article.
-
Enhancing the Signal-to-Noise of Diagnostic Fragment Ions of Unsaturated Glycerophospholipids via Precursor Exclusion Ultraviolet Photodissociation Mass Spectrometry (PEx-UVPD-MS).Anal Chem. 2022 Aug 16;94(32):11352-11359. doi: 10.1021/acs.analchem.2c02128. Epub 2022 Aug 2. Anal Chem. 2022. PMID: 35917227 Free PMC article.
References
-
- Bione S, D’Adamo P, Maestrini E, Gedeon AK, Bolhuis PA, Toniolo D. A novel X-linked gene, G4.5. is responsible for Barth syndrome. Nat Genet. 1996;12:385–389. - PubMed
-
- Xu Y, Kelley RI, Blanck TJ, Schlame M. Remodeling of cardiolipin by phospholipid transacylation. J Biol Chem. 2003;278:51380–51385. - PubMed
-
- Xu Y, Malhotra A, Ren M, Schlame M. The enzymatic function of tafazzin. J Biol Chem. 2006;281:39217–39224. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials