Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy.

TitleChronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy.
Publication TypeJournal Article
Year of Publication2011
AuthorsDi Meo, I, Fagiolari, G, Prelle, A, Viscomi, C, Zeviani, M, Tiranti, V
JournalAntioxid Redox Signal
Volume15
Issue2
Pagination353-62
Date Published2011 Jul 15
ISSN1557-7716
KeywordsAnimals, Blotting, Western, Brain Diseases, Metabolic, Inborn, Cell Line, Dioxygenases, Electron Transport Complex IV, Humans, Mice, Mice, Knockout, Mitochondrial Proteins, Polymerase Chain Reaction, Purpura, Sulfides
Abstract

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.

DOI10.1089/ars.2010.3520
Alternate JournalAntioxid. Redox Signal.
Citation Key10.1089/ars.2010.3520
PubMed ID20812865
Grant ListGGP07019 / / Telethon / Italy
GTF07004 / / Telethon / Italy