Differential metabolic consequences of fumarate hydratase and respiratory chain defects
Differential metabolic consequences of fumarate hydratase and respiratory chain defects
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DOI：
10.1016/j.bbadis.2008.01.008
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发表时间：
2008-05-01
影响因子：
6.2
通讯作者：
Suomalainen, Anu
中科院分区：
文献类型：
--
作者：
Raimundo, Nuno;Ahtinen, Jouni;Suomalainen, Anu
氧化ATP产生途径的缺陷导致了惊人的多种疾病表型，从儿童脑肌病到遗传性肿瘤形成。三羧酸循环的关键酶，富马酸水合酶（FH），参与脑病，但也在平滑肌瘤形成，偶尔也在各种类型的癌症。MELAS（线粒体脑肌病、乳酸酸中毒和中风样发作）和NARP（神经病共济失调视网膜色素变性）是由线粒体DNA突变和呼吸链（RC）缺陷引起的进行性神经系统疾病。这些疾病会导致残疾和过早死亡，但不会导致肿瘤发生。我们研究了FH和RC缺陷的细胞后果，旨在确定能量代谢缺陷的一般反应和FH缺陷的特异性反应，这些反应与肿瘤发生密切相关。与RC缺陷不同，FH缺陷二倍体人成纤维细胞没有表现出氧化应激的迹象，但具有还原的氧化还原状态和高谷胱甘肽水平。细胞质FH同种型，先前描述的，但与一个未知的功能，是完全缺乏在所有FH-缺陷系。富马酸在我们的两个FH系中增加，但未检测到HIF-1 α的积累。在MELAS和FH缺乏症中均诱导糖酵解。富马酸盐在原代成纤维细胞中的蓄积未激活缺氧反应，表明富马酸盐蓄积引起的缺氧激活可能是一种组织特异性反应。缺乏FH的细胞质形式和还原的氧化还原环境是典型的所有FH突变株，其在FH相关的肿瘤发生中的作用需要进一步关注。(c)2008 Elsevier B. V.保留所有权利。
Defects of the oxidative ATP production pathway lead to an amazing variety of disease phenotypes, ranging from childhood encephalomyopathies to hereditary tumor formation. A key enzyme of tricarboxylic cycle, fumarate hydratase (FH), is involved in encephalopathies, but also in leiomyoma formation, and occasionally also in various types of cancer. MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) and NARP (neuropathy ataxia retinitis pigmentosa) are progressive neurological disorders, caused by mitochondrial DNA mutations and respiratory chain (RC) deficiency. These diseases lead to disability and premature death, but not to tumorigenesis. We studied the cellular consequences of FH and RC deficiencies, aiming to identify general responses to energy metabolism defect and those specific for FH-deficiency, suggestively connected to tumorigenesis. Unlike in RC deficiency, the FH-deficient diploid human fibroblasts showed no signs of oxidative stress, but had a reduced redox state with high glutathione levels. The cytoplasmic FH isoform, previously described, but with an unknown function, was completely lacking in all FH-deficient lines. Fumarate was increased in two of our FH-lines, but accumulation of HIF-1 alpha was not detected. Glycolysis was induced in both MELAS and in FH-deficiency. Accumulation of fumarate in primary fibroblasts did not activate a hypoxia response, suggesting that hypoxia activation due to fumarate accumulation may be a tissue-specific response. The lack of cytoplasmic form of FH and the reduced redox environment were typical for all FH-mutant lines, and their role in FH-related tumorigenesis requires further attention. (c) 2008 Elsevier B.V. All rights reserved.