Oyarbide Usua, Anderson Rebecca A, Radzikh Igor, Kodger Jillian V, Patil Akshay S, Staton Morgan, Mulya Anny, Crane Genevieve M, Litovsky Silvio, Sandlers Yana, Corey Seth J
Departments of Pediatrics and Cancer Biology, Lerner Research Institute and Cleveland Clinic, Cleveland, OH.
Department of Chemistry, Cleveland State University, Cleveland, OH.
Res Sq. 2025 Apr 24:rs.3.rs-5960642. doi: 10.21203/rs.3.rs-5960642/v1.
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 , 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 -deficient zebrafish. Neutropenia developed 5 days post-fertilization, but surprisingly no cardiac or skeletal myopathies were detected into adulthood. 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 mutants exhibited a higher number of neutrophils compared to wildtype fish. Further investigation revealed signs of inflammation as evidenced by elevated levels of in the whole kidney marrows and hearts of adult fish. Our comprehensive studies demonstrated that while mitochondrial dysfunction and metabolic defects were evident in -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.
巴斯综合征是一种X连锁综合征，其特征为心肌病、骨骼肌病和中性粒细胞减少。这种危及生命的疾病是由编码位于线粒体内膜的磷脂 - 溶血磷脂转酰基酶的 功能丧失性突变引起的。心磷脂水平降低和单溶血心磷脂水平升高会扰乱线粒体功能。然而，导致肌病和中性粒细胞减少的机制尚不清楚，目前也没有有效的治疗方法。为了填补这些知识空白，我们培育了 缺陷型斑马鱼。受精后5天出现中性粒细胞减少，但令人惊讶的是，成年后未检测到心脏或骨骼肌病。 突变体表现出多种代谢紊乱，类似于患有巴斯综合征的人类所观察到的情况。这些包括单溶血心磷脂与心磷脂的比例增加、3 - 甲基戊二酸水平升高、ATP生成减少、乳酸水平升高和低血糖。对氨基酸和不饱和脂肪酸合成也有广泛影响。尽管存在这些代谢紊乱，斑马鱼的寿命和生育能力正常。在幼虫和成年组织中均检测到心磷脂异常，特别是在心脏和整个肾脏骨髓中。令人惊讶的是，与野生型鱼相比，成年 突变体的中性粒细胞数量更多。进一步研究发现成年鱼的整个肾脏骨髓和心脏中 水平升高，证明存在炎症迹象。我们的综合研究表明，虽然 缺陷型斑马鱼存在线粒体功能障碍和代谢缺陷，但这些紊乱并未显著影响它们的发育和生存。这些发现表明，斑马鱼可能拥有补偿塔法辛缺失的挽救途径，或者人类对TAFAZZIN的缺失具有独特的易感性。
