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<p>Barth syndrome is an X-linked syndrome characterized by cardiomyopathy, skeletal myopathy, and neutropenia. This life-threatening disorder results from loss-of-function mutations in <i>TAFAZZIN</i>, 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 no currently effective therapy exists. To address these knowledge gaps, we generated <i>tafazzin</i>-deficient zebrafish. Neutropenia developed 5 days post-fertilization, but surprisingly no cardiac or skeletal myopathies were detected into adulthood. <i>tafazzin</i> mutants displayed multiple metabolic disturbances like those observed in humans with Barth syndrome. These include increased monolysocardiolipin: Cardiolipin ratios, high levels of 3-methylglutaconic acid, decreased ATP production, increased levels of lactic acid, and hypoglycemia. There were also widespread effects on amino acid and unsaturated fatty acid synthesis. Despite these metabolic disturbances, 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 <i>tafazzin</i> mutants exhibited a higher number of neutrophils compared to wildtype fish. Further investigation revealed signs of inflammation as evidenced by elevated levels of <i>il6</i> in the whole kidney marrows and hearts of adult fish. Our comprehensive studies demonstrated that while mitochondrial dysfunction and metabolic defects were evident in <i>tafazzin</i>-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.</p>

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Tafazzin-deficient zebrafish display mitochondrial dysfunction, neutropenia, and metabolic defects without myopathy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月2日

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  • Usua Oyarbide,
  • Rebecca A. Anderson,
  • Igor Radzikh,
  • Jillian V. Kodger,
  • Akshay S. Patil,
  • Morgan Staton,
  • Anny Mulya,
  • Genevieve M. Crane,
  • Silvio Litovsky,
  • Yana Sandlers,
  • Seth J. Corey

摘要

Barth syndrome is an 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 no currently effective therapy exists. To address these knowledge gaps, we generated tafazzin-deficient zebrafish. Neutropenia developed 5 days post-fertilization, but surprisingly no cardiac or skeletal myopathies were detected into adulthood. tafazzin mutants displayed multiple metabolic disturbances like those observed in humans with Barth syndrome. These include increased monolysocardiolipin: Cardiolipin ratios, high levels of 3-methylglutaconic acid, decreased ATP production, increased levels of lactic acid, and hypoglycemia. There were also widespread effects on amino acid and unsaturated fatty acid synthesis. Despite these metabolic disturbances, 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.