Metabolic response to Parkinson's disease recapitulated by the haploinsufficient diploid yeast cells hemizygous for the adrenodoxin reductase gene.
Metabolic response to Parkinson's disease recapitulated by the haploinsufficient diploid yeast cells hemizygous for the adrenodoxin reductase gene.
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DOI：
10.1039/c9mo00090a
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发表时间：
2019-10
期刊：
影响因子：
2.9
通讯作者：
Duygu Dikicioglu;J. Coxon;S. Oliver
中科院分区：
文献类型：
--
作者：
Duygu Dikicioglu;J. Coxon;S. Oliver
肾上腺素还原酶是一种广泛保守的线粒体P450蛋白，催化类固醇激素生物合成的关键步骤，在肾上腺皮质高表达。酵母肾上腺素还原酶同系物Arh1p参与细胞质和线粒体铁的动态平衡，是含有Fe-S簇的酶活性所必需的。在本文中，我们研究了酵母对ARH1单拷贝缺失的反应，ARH1是线粒体内膜的一种氧化还原酶，是为数不多的对酵母生存至关重要的线粒体蛋白质之一。表型、转录、蛋白质组和代谢图谱表明，酿酒酵母成功地适应了这种损失，表现出明显的剂量不敏感的细胞反应。然而，一项对ARH1受损酵母转录调控的深思熟虑的研究强调，发生了显著的分级重组，涉及铁的同化和酪氨酸的生物合成过程。铁和酪氨酸途径的相互联系的作用，再加上氧化过程，比酵母更令人感兴趣，因为它们参与了与帕金森病相关的多巴胺能神经退化。在酵母中发现类似的反应，虽然是初步的，表明这种简单的真核生物可能作为一个模式系统来研究导致人类早期疾病反应开始和发展的调控机制。
Adrenodoxin reductase, a widely conserved mitochondrial P450 protein, catalyses essential steps in steroid hormone biosynthesis and is highly expressed in the adrenal cortex. The yeast adrenodoxin reductase homolog, Arh1p, is involved in cytoplasmic and mitochondrial iron homeostasis and is required for activity of enzymes containing an Fe-S cluster. In this paper, we investigated the response of yeast to the loss of a single copy of ARH1, an oxidoreductase of the mitochondrial inner membrane, which is among the few mitochondrial proteins that is essential for viability in yeast. The phenotypic, transcriptional, proteomic, and metabolic landscape indicated that Saccharomyces cerevisiae successfully adapted to this loss, displaying an apparently dosage-insensitive cellular response. However, a considered investigation of transcriptional regulation in ARH1-impaired yeast highlighted that a significant hierarchical reorganisation occurred, involving the iron assimilation and tyrosine biosynthetic processes. The interconnected roles of the iron and tyrosine pathways, coupled with oxidative processes, are of interest beyond yeast since they are involved in dopaminergic neurodegeneration associated with Parkinson's disease. The identification of similar responses in yeast, albeit preliminary, suggests that this simple eukaryote could have potential as a model system for investigating the regulatory mechanisms leading to the initiation and progression of early disease responses in humans.