Increased mtDNA Abundance and Improved Function in Human Barth Syndrome Patient Fibroblasts Following AAV-TAZ Gene Delivery

International Journal of Molecular Sciences

Mughil Sriramvenugopal¹  BarryJ. Byrne¹  ChristinaA. Pacak¹  Manash Ramanathan¹  PeterB. Kang¹  Silveli Suzuki-Hatano¹  Meghan Soustek¹  W.Todd Cade² 

[1] Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610, USA;Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO 63110, USA;

关键词: Barth syndrome;    mitochondrial disease;    mtDNA copy numbers;    gene therapy;    AAV;    TMEM65;    fibroblasts;   

DOI  :  10.3390/ijms20143416

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown