Succinate Dehydrogenase: Biogenesis and Role in Disease

描述(申请人提供)：琥珀酸脱氢酶(SDH)是线粒体呼吸链和三元酸循环中不可或缺的组成部分。这种酶包含四个亚基和无数的氧化还原辅因子，需要组装因子来促进蛋白质组装和辅因子插入。我们建议揭示形成活性SDH所需的三个新的组装因子的分子功能。在酵母中的机械生物化学和遗传学之后，培养的哺乳动物细胞的研究，以提供SDH组装因子的功能的全面图景。初步研究表明，Sdh6(SDHAF1)和Acn9具有与SDH铁硫簇亚基Sdh2成熟相关的非冗余功能。拟议的研究将测试这两个因素是否有助于铁-硫簇转移到Sdh2，伴侣holo-Sdh2转移到成熟的四聚体酶中，或者促进受损铁-硫簇的修复。对第三组装因子Sdh8的初步研究表明，它在催化Sdh1亚基的组装中起作用。提案中概述的研究将阐明SDH组装中Sdh8/Sdh1复合体的性质和功能。我们还建议探索这些因子的突变或失调在人类SDH缺乏症中的作用。SDH装配障碍会导致多种病理改变，包括白质脑病、Leigh综合征、小脑萎缩和肿瘤的发生。我们试图揭示这些新的组装因子与人类SDH缺乏性疾病之间的强烈预测关联。我们推测，其他SDH组装因子仍有待发现，其中一些可能是这些先前特发性SDH缺陷疾病的易感基因。

DESCRIPTION (provided by applicant): Succinate dehydrogenase (SDH) is an integral component of the mitochondrial respiratory chain and tricarboxylic acid cycle. The enzyme, containing four subunits and a myriad of redox cofactors, requires assembly factors to facilitate protein assembly and cofactor insertion. We propose to uncover the molecular function of three novel assembly factors required for the formation of active SDH. Mechanistic biochemistry and genetics in yeast are followed by studies in cultured mammalian cells to provide a comprehensive picture of the function of SDH assembly factors. Preliminary studies indicate that Sdh6 (SDHAF1) and Acn9 perform non-redundant functions related to the maturation of the iron-sulfur cluster subunit Sdh2 of SDH. Proposed studies will test whether these two factors facilitate transfer of iron-sulfur clusters to Sdh2, chaperone holo - Sdh2 into the mature tetrameric enzyme or mediate repair of damaged iron-sulfur clusters. Preliminary studies on the third assembly factor Sdh8 showed a role in the assembly of the catalytic Sdh1 subunit. Studies outlined in the proposal will elucidate the nature and function of the Sdh8/Sdh1 complex in the assembly of SDH. We also propose to explore the roles of mutations or dysregulation of these factors in human SDH deficiency disorders. Disorders arising from impaired assembly of SDH result in a variety of pathologies, including leukoencephalopathy, Leigh syndrome, cerebellar atrophy and tumorigenesis. We seek to uncover strongly predicted associations of these novel assembly factors with human SDH-deficiency diseases. We hypothesize that additional SDH assembly factors remain to be discovered, some of which may be susceptibility genes for these previously idiopathic SDH-deficient diseases.