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.
Highlights
Barth syndrome (BTHS) is a rare mitochondrial disorder caused by recessive loss-of-function mutations in the nuclear-encoded gene TAZ, which encodes tafazzin
The two BTHS fibroblasts lines used in this study represent either a missense mutation (BTHS1) or a deletion with frameshift leading to premature stop (BTHS2) (Table 1)
This study demonstrates that the reduced mtDNA copy numbers observed in primary BTHS patient dermal fibroblasts can be efficiently recovered following associated virus (AAV)-mediated TAZ gene replacement
Summary
Barth syndrome (BTHS) is a rare mitochondrial disorder caused by recessive loss-of-function mutations in the nuclear-encoded gene TAZ, which encodes tafazzin. Tafazzin is an acyltransferase that is trafficked to the inner mitochondrial membrane (IMM) where it remodels monolysocardiolipin (MLCL) to mature cardiolipin (CL) [1,2]. Typical BTHS symptoms include cardioskeletal myopathy, impaired cardiac and skeletal muscle bioenergetics, neutropenia, and 3-methylglutaconic aciduria, with cardiomyopathy being the primary cause of death [10,11,12,13,14,15,16]. The structural integrity of the IMM is known to be impaired in BTHS, investigations into levels of mtDNA copy numbers in BTHS and whether these levels successfully recover following a gene replacement strategy in BTHS patient-derived cells have not yet been performed
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