Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for Research on Children's Mitochondrial Disorders, Institute of Neurology Carlo Besta-IRCCS Foundation, Milan, Italy.
Antioxid Redox Signal. 2011 Jul 15;15(2):353-62. doi: 10.1089/ars.2010.3520. Epub 2011 Feb 25.
Ethylmalonic encephalopathy (EE) is an autosomal recessive, invariably fatal disorder associated with mutations in ETHE1, a gene encoding a mitochondrial sulfur dioxygenase (SDO). The main consequence of the absence of Ethe1-SDO is the accumulation of sulfide (H(2)S) in critical tissues, including colonic mucosa, liver, muscle, and brain. To make progress in the elucidation of the biochemical mechanisms leading to cytochrome c oxidase (COX) deficiency, we (i) generated tissue-specific conditional Ethe1 knockout mice to clarify the different contributions of endogenous and exogenous H(2)S production, and (ii) studied the development of H(2)S-driven COX deficiency in Ethe1(-/-) mouse tissues and human cells. Ethe1(-/-) conditional animals displayed COX deficiency limited to the specific targeted tissue. The accumulation of H(2)S over time causes progressive COX deficiency in animal tissues and human cells, which is associated with reduced amount of COX holoenzyme, and of several COX subunits, including mitochondrially encoded cytochrome c oxidase 1 (MTCO1), MTCO2, COX4, and COX5A. This reduction is not paralleled by consistent downregulation in expression of the corresponding mRNAs. Tissue-specific ablation of Ethe1 causes COX deficiency in targeted organs, suggesting that failure in neutralizing endogenous, tissue-specific production of H(2)S is sufficient to cause the biochemical defect but neither to determine a clinical impact nor to induce the biomarker profile typical of EE. The mechanism by which H(2)S causes COX deficiency consists of rapid heme a inhibition and accelerated long-term degradation of COX subunits. However, the pleiotropic devastating effects of H(2)S accumulation in EE cannot be fully explained by the sole defect of COX in critical tissues, but are likely consequent to several toxic actions on a number of enzymatic activities in different tissues, including endothelial lining of the small vessels, leading to multiorgan failure.
乙基丙二酸脑病 (EE) 是一种常染色体隐性、致命的疾病，与编码线粒体硫双加氧酶 (SDO) 的 ETHE1 基因突变有关。Ethe1-SDO 缺失的主要后果是包括结肠黏膜、肝脏、肌肉和大脑在内的关键组织中硫化物 (H₂S) 的积累。为了在阐明导致细胞色素 c 氧化酶 (COX) 缺乏的生化机制方面取得进展，我们 (i) 生成组织特异性条件性 Ethe1 敲除小鼠，以阐明内源性和外源性 H₂S 产生的不同贡献，和 (ii) 研究 Ethe1(-/-) 小鼠组织和人细胞中 H₂S 驱动的 COX 缺乏的发展。Ethe1(-/-) 条件性动物表现出仅限于特定靶向组织的 COX 缺乏。随着时间的推移，H₂S 的积累导致动物组织和人细胞中 COX 缺乏的进行性进展，这与 COX 全酶和几个 COX 亚基的减少有关，包括线粒体编码的细胞色素 c 氧化酶 1 (MTCO1)、MTCO2、COX4 和 COX5A。这种减少与相应 mRNA 的表达一致下调无关。Ethe1 的组织特异性缺失导致靶向器官中的 COX 缺乏，表明中和内源性、组织特异性 H₂S 产生的失败足以引起生化缺陷，但既不能确定临床影响，也不能诱导 EE 的典型生物标志物谱。H₂S 引起 COX 缺乏的机制包括血红素 a 的快速抑制和 COX 亚基的长期加速降解。然而，EE 中 H₂S 积累的多效破坏性影响不能仅通过 COX 在关键组织中的缺陷来完全解释，而是可能归因于对不同组织中许多酶活性的多种毒性作用，包括小血管的内皮衬里，导致多器官衰竭。
