A computational screen for regulators of oxidative phosphorylation implicates SLIRP in mitochondrial RNA homeostasis.
A computational screen for regulators of oxidative phosphorylation implicates SLIRP in mitochondrial RNA homeostasis.
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DOI：
10.1371/journal.pgen.1000590
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发表时间：
2009-08
期刊：
影响因子：
4.5
通讯作者：
Mootha VK
中科院分区：
文献类型：
--
作者：
Baughman JM;Nilsson R;Gohil VM;Arlow DH;Gauhar Z;Mootha VK
人类氧化磷酸化（OxPhos）系统由大约90种由核和线粒体基因组编码的蛋白质组成，并作为ATP生物合成的主要细胞途径。虽然OxPhos的核心蛋白质机制已得到很好的表征，但其许多组装、成熟和调节因子仍未知。我们利用编码核心OxPhos机制的基因的严格转录控制来鉴定新的调节剂。我们开发了一种计算程序，我们称之为表达筛选，它以原则性的方式整合了来自数千个微阵列数据集的信息，以识别在生物学背景下与靶途径一致共表达的基因。我们应用表达筛选来预测数十种OxPhos的新型调节剂。对于两个候选基因，CHCHD2和SLIRP，我们表明，沉默与RNAi的结果在不稳定的OxPhos复合物和OxPhos酶活性的显着损失。此外，我们表明，SLIRP在维持大脑定位的mRNA转录编码OxPhos蛋白亚基中起着至关重要的作用。我们的研究结果提供了一个潜在的新型OxPhos调节剂的目录，促进了我们对细胞能量代谢调节的核和线粒体基因组之间协调的理解。呼吸链疾病是最大的一类先天性代谢缺陷，每5 000人中就有1人受到影响。从生物化学上讲，这些疾病的特征是称为氧化磷酸化（OxPhos）的细胞过程的破坏，氧化磷酸化负责以ATP的形式产生细胞的大部分能量。可悲的是，对于大约50%的确诊患者，我们不知道这些疾病背后的分子原因。我们有限的诊断能力的一个可能原因是，这些患者在一个基因中含有突变，该基因不知道在OxPhos通路中起作用。因此，我们设计了一种称为表达筛选的计算策略，该策略整合了公开的全基因组基因表达数据，以预测可能在OxPhos生物学中发挥作用的新基因。我们确定了几个未表征的基因，我们的程序强烈预测在OxPhos途径中发挥作用，并通过实验验证了两个基因，SLIRP和CHCHD2，作为OxPhos功能所必需的。这些基因以及通过表达筛选预测的调节OxPhos的其他基因代表了用于鉴定呼吸链疾病的分子基础的宝贵资源。
The human oxidative phosphorylation (OxPhos) system consists of approximately 90 proteins encoded by nuclear and mitochondrial genomes and serves as the primary cellular pathway for ATP biosynthesis. While the core protein machinery for OxPhos is well characterized, many of its assembly, maturation, and regulatory factors remain unknown. We exploited the tight transcriptional control of the genes encoding the core OxPhos machinery to identify novel regulators. We developed a computational procedure, which we call expression screening, which integrates information from thousands of microarray data sets in a principled manner to identify genes that are consistently co-expressed with a target pathway across biological contexts. We applied expression screening to predict dozens of novel regulators of OxPhos. For two candidate genes, CHCHD2 and SLIRP, we show that silencing with RNAi results in destabilization of OxPhos complexes and a marked loss of OxPhos enzymatic activity. Moreover, we show that SLIRP plays an essential role in maintaining mitochondrial-localized mRNA transcripts that encode OxPhos protein subunits. Our findings provide a catalogue of potential novel OxPhos regulators that advance our understanding of the coordination between nuclear and mitochondrial genomes for the regulation of cellular energy metabolism. Respiratory chain disorders represent the largest class of inborn errors in metabolism affecting 1 in every 5,000 individuals. Biochemically, these disorders are characterized by a breakdown in the cellular process called oxidative phosphorylation (OxPhos), which is responsible for generating most of the cell's energy in the form of ATP. Sadly, for approximately 50% of patients diagnosed, we do not know the molecular cause behind these disorders. One possible reason for our limited diagnostic capability is that these patients harbor a mutation in a gene that is not known to act in the OxPhos pathway. We therefore designed a computational strategy called expression screening that integrates publicly available genome-wide gene expression data to predict new genes that may play a role in OxPhos biology. We identified several uncharacterized genes that were strongly predicted by our procedure to function in the OxPhos pathway and experimentally validated two genes, SLIRP and CHCHD2, as being essential for OxPhos function. These genes, as well as others predicted by expression screening to regulate OxPhos, represent a valuable resource for identifying the molecular underpinnings of respiratory chain disorders.
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