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Pathogenic mutations of the human mitochondrial citrate carrier SLC25A1 lead to impaired citrate export required for lipid, dolichol, ubiquinone and sterol synthesis.

Accepted version
Peer-reviewed

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Article

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Authors

Majd, Homa 
King, Martin S 
Smith, Anthony C 
Kunji, Edmund RS 

Abstract

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.

Description

Keywords

Citrate metabolism, Mitochondrial carriers, Mitochondrial disease, Mitochondrial tricarboxylate carrier, Structure-function relationships, Transport, Anion Transport Proteins, Biological Transport, Active, Brain Diseases, Metabolic, Inborn, Catalytic Domain, Citric Acid, Computer Simulation, Dolichols, Humans, Mitochondrial Proteins, Models, Biological, Mutation, Missense, Organic Anion Transporters, Sterols, Ubiquinone

Journal Title

Biochim Biophys Acta Bioenerg

Conference Name

Journal ISSN

0005-2728
1879-2650

Volume Title

1859

Publisher

Elsevier BV
Sponsorship
Medical Research Council (MC_U105663139)
Biotechnology and Biological Sciences Research Council (BB/R50564X/1)
Medical Research Council (MC_UU_00015/1)
Medical Research Council (MC_U105674181)
Medical Research Council (MC_UU_00015/7)