Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies
- PMID: 24813252
- PMCID: PMC4172922
- DOI: 10.1038/nm.3545
Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies
Abstract
Study of monogenic mitochondrial cardiomyopathies may yield insights into mitochondrial roles in cardiac development and disease. Here, we combined patient-derived and genetically engineered induced pluripotent stem cells (iPSCs) with tissue engineering to elucidate the pathophysiology underlying the cardiomyopathy of Barth syndrome (BTHS), a mitochondrial disorder caused by mutation of the gene encoding tafazzin (TAZ). Using BTHS iPSC-derived cardiomyocytes (iPSC-CMs), we defined metabolic, structural and functional abnormalities associated with TAZ mutation. BTHS iPSC-CMs assembled sparse and irregular sarcomeres, and engineered BTHS 'heart-on-chip' tissues contracted weakly. Gene replacement and genome editing demonstrated that TAZ mutation is necessary and sufficient for these phenotypes. Sarcomere assembly and myocardial contraction abnormalities occurred in the context of normal whole-cell ATP levels. Excess levels of reactive oxygen species mechanistically linked TAZ mutation to impaired cardiomyocyte function. Our study provides new insights into the pathogenesis of Barth syndrome, suggests new treatment strategies and advances iPSC-based in vitro modeling of cardiomyopathy.
Figures
![Fig. 1](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/4172922/bin/nihms579142f1.gif)
![Fig. 2](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/4172922/bin/nihms579142f2.gif)
![Fig. 3](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/4172922/bin/nihms579142f3.gif)
![Figure 4](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/4172922/bin/nihms579142f4.gif)
![Figure 5](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/4172922/bin/nihms579142f5.gif)
![Fig. 6](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/4172922/bin/nihms579142f6.gif)
Comment in
-
Cardiomyopathy, mitochondria and Barth syndrome: iPSCs reveal a connection.Nat Med. 2014 Jun;20(6):585-6. doi: 10.1038/nm.3592. Nat Med. 2014. PMID: 24901565 No abstract available.
-
Your heart on a chip: iPSC-based modeling of Barth-syndrome-associated cardiomyopathy.Cell Stem Cell. 2014 Jul 3;15(1):9-11. doi: 10.1016/j.stem.2014.06.015. Cell Stem Cell. 2014. PMID: 24996164
Similar articles
-
Increased Reactive Oxygen Species-Mediated Ca2+/Calmodulin-Dependent Protein Kinase II Activation Contributes to Calcium Handling Abnormalities and Impaired Contraction in Barth Syndrome.Circulation. 2021 May 11;143(19):1894-1911. doi: 10.1161/CIRCULATIONAHA.120.048698. Epub 2021 Apr 1. Circulation. 2021. PMID: 33793303 Free PMC article.
-
Barth Syndrome: From Mitochondrial Dysfunctions Associated with Aberrant Production of Reactive Oxygen Species to Pluripotent Stem Cell Studies.Front Genet. 2016 Jan 20;6:359. doi: 10.3389/fgene.2015.00359. eCollection 2015. Front Genet. 2016. PMID: 26834781 Free PMC article. Review.
-
Your heart on a chip: iPSC-based modeling of Barth-syndrome-associated cardiomyopathy.Cell Stem Cell. 2014 Jul 3;15(1):9-11. doi: 10.1016/j.stem.2014.06.015. Cell Stem Cell. 2014. PMID: 24996164
-
Cardiomyopathy, mitochondria and Barth syndrome: iPSCs reveal a connection.Nat Med. 2014 Jun;20(6):585-6. doi: 10.1038/nm.3592. Nat Med. 2014. PMID: 24901565 No abstract available.
-
Barth syndrome.Am J Med Genet C Semin Med Genet. 2013 Aug;163C(3):198-205. doi: 10.1002/ajmg.c.31372. Epub 2013 Jul 10. Am J Med Genet C Semin Med Genet. 2013. PMID: 23843353 Free PMC article. Review.
Cited by
-
Engineered platforms for mimicking cardiac development and drug screening.Cell Mol Life Sci. 2024 Apr 25;81(1):197. doi: 10.1007/s00018-024-05231-1. Cell Mol Life Sci. 2024. PMID: 38664263 Free PMC article. Review.
-
Current advances in human-induced pluripotent stem cell-based models and therapeutic approaches for congenital heart disease.Mol Cell Biochem. 2024 Apr 18. doi: 10.1007/s11010-024-04997-z. Online ahead of print. Mol Cell Biochem. 2024. PMID: 38635080 Review.
-
Addressing Cardiovascular Toxicity Risk of Electronic Nicotine Delivery Systems in the Twenty-First Century: "What Are the Tools Needed for the Job?" and "Do We Have Them?".Cardiovasc Toxicol. 2024 May;24(5):435-471. doi: 10.1007/s12012-024-09850-9. Epub 2024 Mar 31. Cardiovasc Toxicol. 2024. PMID: 38555547 Review.
-
The new era of cardiovascular research: revolutionizing cardiovascular research with 3D models in a dish.Med Rev (2021). 2024 Feb 20;4(1):68-85. doi: 10.1515/mr-2023-0059. eCollection 2024 Feb. Med Rev (2021). 2024. PMID: 38515776 Free PMC article. Review.
-
Temporal Effects of Safflower Oil Diet-Based Linoleic Acid Supplementation on Barth Syndrome Cardiomyopathy.Circulation. 2024 Mar 5;149(10):790-793. doi: 10.1161/CIRCULATIONAHA.123.065414. Epub 2024 Mar 4. Circulation. 2024. PMID: 38437482 No abstract available.
References
-
- Bione S, et al. A novel X-linked gene, G4.5. is responsible for Barth syndrome. Nat Genet. 1996;12:385–389. - PubMed
-
- Houtkooper RH, et al. The enigmatic role of tafazzin in cardiolipin metabolism. Biochim Biophys Acta. 2009;1788:2003–2014. - PubMed
-
- Chicco AJ, Sparagna GC. Role of cardiolipin alterations in mitochondrial dysfunction and disease. Am J Physiol Cell Physiol. 2007;292:C33–C44. - PubMed
-
- Kariko K, Buckstein M, Ni H, Weissman D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity. 2005;23:165–175. - PubMed
Online Methods References
-
- Chan EM, et al. Live cell imaging distinguishes bona fide human iPS cells from partially reprogrammed cells. Nat Biotechnol. 2009;27:1033–1037. - PubMed
-
- Ichida F, et al. Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome. Circulation. 2001;103:1256–1263. - PubMed
-
- Whitman GJ, et al. Diagnosis and therapeutic evaluation of a pediatric case of cardiomyopathy using phosphorus-31 nuclear magnetic resonance spectroscopy. J Am Coll Cardiol. 1985;5:745–749. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials