Tafazzin-Deficient Zebrafish Display Mitochondrial Dysfunction and Metabolic Defects Without Myopathy
Barth syndrome is a rare X-linked syndrome characterized by cardiomyopathy, skeletal myopathy, and neutropenia. This life-threatening disorder results from loss of function mutations in TAFAZZIN, which encodes a phospholipid-lysophospholipid transacylase located in the mitochondria inner membrane. Decreased cardiolipin levels and increased monolysocardiolipin levels perturb mitochondrial function. However, the mechanism(s) leading to myopathies and neutropenia are unknown, and there is currently no effective therapy for Barth syndrome. To address these knowledge gaps, we generated tafazzin-deficient zebrafish. Neutropenia developed as early as 5 days post-fertilization, but surprisingly no cardiac or skeletal myopathies were detected into adulthood. Yet, mitochondrial dysfunction in tafazzin mutants led to decreased ATP production. Metabolomic analysis revealed notable changes, including increased levels of lactic acid, decreased glucose, and widespread effects on amino acid and unsaturated fatty acid synthesis. Despite these metabolic disturbances, the zebrafish displayed a normal lifespan and fertility. Cardiolipin abnormalities were detected in both larvae and adult tissues, specifically in the heart and whole kidney marrow. Surprisingly, adult tafazzin mutants exhibited a higher number of neutrophils compared to wildtype fish. Further investigation revealed signs of inflammation as evidenced by elevated levels of il6 in the whole kidney marrows and hearts of adult fish. Our comprehensive studies demonstrated that while mitochondrial dysfunction and metabolic defects were evident in tafazzin-deficient zebrafish, these disturbances did not significantly affect their development nor survival. These findings suggest that zebrafish may possess salvage pathways which compensate for Tafazzin loss or that humans have a unique vulnerability to the loss of TAFAZZIN. Overall design: RNA was extracted from pools of 25 larvae at 5 dpf using TRIzol reagent. Three pools of maternal zygotic tafazzin mutants and 3 pools of wild-type from the same clutch were compared. RNA quality was determined by Bioanalyzer (Agilent)