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| [PMID]: | 29031613 |
| [Au] Autor: | Majd H; King MS; Smith AC; Kunji ERS |
| [Ad] Endereço: | Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK. |
| [Ti] Título: | Pathogenic mutations of the human mitochondrial citrate carrier SLC25A1 lead to impaired citrate export required for lipid, dolichol, ubiquinone and sterol synthesis. |
| [So] Source: | Biochim Biophys Acta;1859(1):1-7, 2018 01. | | [Is] ISSN: | 0006-3002 |
| [Cp] País de publicação: | Netherlands |
| [La] Idioma: | eng |
| [Ab] Resumo: | Missense mutations of the human mitochondrial citrate carrier, encoded by the SLC25A1 gene, lead to an autosomal recessive neurometabolic disorder characterised by neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development, often resulting in early death. Here, we have measured the effect of all twelve known pathogenic mutations on the transport activity. The results show that nine mutations abolish transport of citrate completely, whereas the other three reduce the transport rate by >70%, indicating that impaired citrate transport is the most likely primary cause of the disease. Some mutations may be detrimental to the structure of the carrier, whereas others may impair key functional elements, such as the substrate binding site and the salt bridge network on the matrix side of the carrier. To understand the consequences of impaired citrate transport on metabolism, the substrate specificity was also determined, showing that the human citrate carrier predominantly transports citrate, isocitrate, cis-aconitate, phosphoenolpyruvate and malate. Although D-2- and L-2 hydroxyglutaric aciduria is a metabolic hallmark of the disease, it is unlikely that the citrate carrier plays a significant role in the removal of hydroxyglutarate from the cytosol for oxidation to oxoglutarate in the mitochondrial matrix. In contrast, computer simulations of central metabolism predict that the export of citrate from the mitochondrion cannot be fully compensated by other pathways, restricting the cytosolic production of acetyl-CoA that is required for the synthesis of lipids, sterols, dolichols and ubiquinone, which in turn explains the severe disease phenotypes. |
| [Mh] Termos MeSH primário: |
Proteínas de Transporte de Ânions
Ácido Cítrico/metabolismo
Simulação por Computador
Dolicol
Proteínas Mitocondriais
Modelos Biológicos
Mutação de Sentido Incorreto
Esteróis
Ubiquinona
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| [Mh] Termos MeSH secundário: |
Proteínas de Transporte de Ânions/química
Proteínas de Transporte de Ânions/genética
Proteínas de Transporte de Ânions/metabolismo
Transporte Biológico Ativo/genética
Encefalopatias Metabólicas Congênitas/enzimologia
Encefalopatias Metabólicas Congênitas/genética
Domínio Catalítico
Dolicol/biossíntese
Dolicol/química
Dolicol/genética
Seres Humanos
Proteínas Mitocondriais/química
Proteínas Mitocondriais/genética
Proteínas Mitocondriais/metabolismo
Esteróis/biossíntese
Esteróis/química
Esteróis/metabolismo
Ubiquinona/biossíntese
Ubiquinona/química
Ubiquinona/genética
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| [Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (Anion Transport Proteins); 0 (Mitochondrial Proteins); 0 (Slc25a1 protein, human); 0 (Sterols); 1339-63-5 (Ubiquinone); 2067-66-5 (Dolichol); 2968PHW8QP (Citric Acid) |
| [Em] Mês de entrada: | 1803 |
| [Cu] Atualização por classe: | 180309 |
[Lr] Data última revisão:
| 180309 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 171017 |
| [St] Status: | MEDLINE |
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