Abstract
Barth syndrome (BTHS) is a rare, X-linked, mitochondrial disorder caused by mutations in the gene encoding tafazzin. BTHS results in cardiomyopathy, muscle fatigue, and neutropenia in patients. Tafazzin is responsible for remodeling cardiolipin, a key structural lipid of the inner mitochondrial membrane. As symptoms can vary in severity amongst BTHS patients, we sought to compare mtDNA copy numbers, mitochondrial fragmentation, and functional parameters between primary dermal BTHS fibroblasts isolated from patients with two different mutations in the TAZ locus. To confirm cause-effect relationships and further support the development of gene therapy for BTHS, we also characterized the BTHS cells following adeno-associated virus (AAV)-TAZ transduction. Our data show that, in response to AAV-TAZ transduction, these remarkably dynamic organelles show recovery of mtDNA copy numbers, mitochondrial structure, and mitochondrial function, providing additional evidence to support the therapeutic potential of AAV-mediated gene delivery for BTHS. This study also demonstrates the direct relationship between healthy mitochondrial membrane structure and maintenance of proper levels of mtDNA copy numbers.
| Original language | English (US) |
|---|---|
| Article number | 3416 |
| Journal | International journal of molecular sciences |
| Volume | 20 |
| Issue number | 14 |
| DOIs | |
| State | Published - Jul 2 2019 |
| Externally published | Yes |
Bibliographical note
Funding Information:Funding: Barth Syndrome Foundation: Association Barth France and the Will McCurdy Fund for the Advancement of Therapies for Barth Syndrome AGR DTD 03-06-2015 (CAP), Barth Syndrome Foundation: Barth Syndrome Foundation of Canada AGR DTD 7-14-2017 (CAP), the American Heart Association-Scientist Development Grant #17SDG33410467 (CAP), the Children’s Miracle Network: UF Pediatrics Pilot Project (CAP), the National Institutes of Health R01 HL136759-01A1 (CAP), and National Institutes of Health R01 HL107406-01A1 (WTC) all provided funding support for this study.
Funding Information:
Barth Syndrome Foundation: Association Barth France and theWill McCurdy Fund for the Advancement of Therapies for Barth Syndrome AGR DTD 03-06-2015 (CAP), Barth Syndrome Foundation: Barth Syndrome Foundation of Canada AGR DTD 7-14-2017 (CAP), the American Heart Association-Scientist Development Grant #17SDG33410467 (CAP), the Children?s Miracle Network: UF Pediatrics Pilot Project (CAP), the National Institutes of Health R01 HL136759-01A1 (CAP), and National Institutes of Health R01 HL107406-01A1 (WTC) all provided funding support for this study. We would like to acknowledge Xiao Xiao (UNC) for sharing the dsAAV vector, the UF Vector Core facility for AAV production, and Arun Srivastava (UF) for sharing the AAV2 triple Y-F mutant capsid. This study was supported by the Robert P. Apkarian Integrated Electron Microscopy Core (IEMC) at Emory University, which is subsidized by the School of Medicine and Emory College of Arts and Sciences. Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under award number UL1TR000454.
Funding Information:
Acknowledgments: We would like to acknowledge Xiao Xiao (UNC) for sharing the dsAAV vector, the UF Vector Core facility for AAV production, and Arun Srivastava (UF) for sharing the AAV2 triple Y–F mutant capsid. This study was supported by the Robert P. Apkarian Integrated Electron Microscopy Core (IEMC) at Emory University, which is subsidized by the School of Medicine and Emory College of Arts and Sciences. Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under award number UL1TR000454.
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
Keywords
- AAV
- Barth syndrome
- Fibroblasts
- Gene therapy
- Mitochondrial disease
- TMEM65
- mtDNA copy numbers