Cardiac metabolic pathways affected in the mouse model of barth syndrome.
Cardiac metabolic pathways affected in the mouse model of barth syndrome.
复制标题
DOI：
10.1371/journal.pone.0128561
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Khuchua Z
中科院分区：
文献类型：
--
作者：
Huang Y;Powers C;Madala SK;Greis KD;Haffey WD;Towbin JA;Purevjav E;Javadov S;Strauss AW;Khuchua Z
心磷脂（Cardiolipin， CL）是一种线粒体磷脂，对电子传递链（ETC）的完整性至关重要。人类的氯缺乏是由他法津（Taz）基因突变引起的，并导致多系统儿科疾病，巴思综合征（BTHS）。据报道，他法嗪缺乏使线粒体呼吸链复合物不稳定并影响超复合物的组装。本研究的目的是研究taz基因敲低对线粒体蛋白质组学景观和代谢过程的影响，如呼吸链超复合物的稳定性及其与心肌脂肪酸氧化酶的相互作用。蛋白质组学分析表明，线粒体呼吸链的几个多肽减少，包括复合体III的Rieske和细胞色素c1亚基，复合体I的NADH脱氢酶α亚基5和F0F1-ATP合成酶的催化核形成亚基。Taz基因敲低导致心脏线粒体中叶酸和氨基酸代谢途径的酶上调，表明Taz缺乏导致心肌的实质性代谢重塑。在Taz基因敲低的心脏中，线粒体呼吸链超复合物在cl -耗尽的线粒体中不稳定，导致ETC与脂肪酸氧化酶，长链酰基辅酶a脱氢酶和长链3-羟基酰基辅酶a脱氢酶之间的相互作用中断，可能影响这两种代谢途径之间还原等量物的代谢通道。在taz基因敲除的心脏中，线粒体结合的肌红蛋白显著减少，可能破坏细胞内氧向氧化磷酸化系统的输送。我们的研究结果确定了受线粒体taz缺陷影响的关键途径，并为BTHS的治疗方案的发展建立了未来的框架。
Cardiolipin (CL) is a mitochondrial phospholipid essential for electron transport chain (ETC) integrity. CL-deficiency in humans is caused by mutations in the tafazzin (Taz) gene and results in a multisystem pediatric disorder, Barth syndrome (BTHS). It has been reported that tafazzin deficiency destabilizes mitochondrial respiratory chain complexes and affects supercomplex assembly. The aim of this study was to investigate the impact of Taz-knockdown on the mitochondrial proteomic landscape and metabolic processes, such as stability of respiratory chain supercomplexes and their interactions with fatty acid oxidation enzymes in cardiac muscle. Proteomic analysis demonstrated reduction of several polypeptides of the mitochondrial respiratory chain, including Rieske and cytochrome c1 subunits of complex III, NADH dehydrogenase alpha subunit 5 of complex I and the catalytic core-forming subunit of F0F1-ATP synthase. Taz gene knockdown resulted in upregulation of enzymes of folate and amino acid metabolic pathways in heart mitochondria, demonstrating that Taz-deficiency causes substantive metabolic remodeling in cardiac muscle. Mitochondrial respiratory chain supercomplexes are destabilized in CL-depleted mitochondria from Taz knockdown hearts resulting in disruption of the interactions between ETC and the fatty acid oxidation enzymes, very long-chain acyl-CoA dehydrogenase and long-chain 3-hydroxyacyl-CoA dehydrogenase, potentially affecting the metabolic channeling of reducing equivalents between these two metabolic pathways. Mitochondria-bound myoglobin was significantly reduced in Taz-knockdown hearts, potentially disrupting intracellular oxygen delivery to the oxidative phosphorylation system. Our results identify the critical pathways affected by the Taz-deficiency in mitochondria and establish a future framework for development of therapeutic options for BTHS.
登录
查看更多内容
影响因子：
6.1
作者：
Liu, Tingting;Chen, Le;Kim, Eunjung;Tran, Diana;Phinney, Brett S.;Knowlton, Anne A.
通讯作者：
Knowlton, Anne A.
影响因子：
4.8
作者：
Acehan, Devrim;Vaz, Frederic;Khuchua, Zaza
通讯作者：
Khuchua, Zaza
影响因子：
13.3
作者：
Jin, Seok Min;Youle, Richard J.
通讯作者：
Youle, Richard J.
影响因子：
6.5
作者：
Kiebish, Michael A.;Yang, Kui;Gross, Richard W.
通讯作者：
Gross, Richard W.
影响因子：
20.1
作者：
Lutucuta, S;Ballantyne, CM;Marian, AJ
通讯作者：
Marian, AJ