A Mitochondrial Pyruvate Carrier Required for Pyruvate Uptake in Yeast,
            <i>Drosophila</i>
            , and Humans

Bricker, Daniel K.; Taylor, Eric B.; Schell, John C.; Orsak, Thomas; Boutron, Audrey; Chen, Yu Chan; Cox, James E.; Cardon, Caleb M.; Vranken, Jonathan G. Van; Dephoure, Noah; Redin, Claire; Boudina, Sihem; Gygi, Steven P.; Brivet, M.; Thummel, Carl S.; Rutter, Jared

doi:10.1126/science.1218099

Cited by 776 publications

(928 citation statements)

References 19 publications

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“…For instance, most of the proteins responsible for the export of lysosomal catabolites remain unknown (3), and the lysosomal chloride transporter, ClC-7, was functionally characterized (6, 7) long after its identification. Even a key protein, such as the pyruvate transporter that fuels mitochondria and links glycolysis to the citric acid cycle, has long remained elusive (8,9). A novel family of transporters that export sugars from plant and animal cells has also been only recently unveiled (10,11).…”

mentioning

confidence: 99%

Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy

Jézégou

Llinares

Anne

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

154

184

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Cystinosin, the lysosomal cystine exporter defective in cystinosis, is the founding member of a family of heptahelical membrane proteins related to bacteriorhodopsin and characterized by a duplicated motif termed the PQ loop. PQ-loop proteins are more frequent in eukaryotes than in prokaryotes; except for cystinosin, their molecular function remains elusive. In this study, we report that three yeast PQ-loop proteins of unknown function, Ypq1, Ypq2, and Ypq3, localize to the vacuolar membrane and are involved in homeostasis of cationic amino acids (CAAs). We also show that PQLC2, a mammalian PQ-loop protein closely related to yeast Ypq proteins, localizes to lysosomes and catalyzes a robust, electrogenic transport that is selective for CAAs and strongly activated at low extracytosolic pH. Heterologous expression of PQLC2 at the yeast vacuole rescues the resistance phenotype of an ypq2 mutant to canavanine, a toxic analog of arginine efficiently transported by PQLC2. Finally, PQLC2 transports a lysine-like mixed disulfide that serves as a chemical intermediate in cysteamine therapy of cystinosis, and PQLC2 gene silencing trapped this intermediate in cystinotic cells. We conclude that PQLC2 and Ypq1–3 proteins are lysosomal/vacuolar exporters of CAAs and suggest that small-molecule transport is a conserved feature of the PQ-loop protein family, in agreement with its distant similarity to SWEET sugar transporters and to the mitochondrial pyruvate carrier. The elucidation of PQLC2 function may help improve cysteamine therapy. It may also clarify the origin of CAA abnormalities in Batten disease.

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mentioning

confidence: 99%

Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy

Jézégou

Llinares

Anne

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

154

184

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“…1d). We thus tested whether the pyruvate carrier inhibitor (UK5099) 23,24 that perturbs entry of pyruvate into the mitochondria would affect acetate generation. As expected, the 13 C labelled Ac-CoA, Ac-carnitine (reversibly converted from Ac-CoA) and citrate (the first intermediate in the TCA cycle) were decreased by UK5099 treatment ( Supplementary Figs.…”

Section: Resultsmentioning

confidence: 99%

De novo acetate production is coupled to central carbon metabolism in mammals

Liu

et al. 2018

Preprint

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In cases of nutritional excess, there is incomplete catabolism of a nutritional source and secretion of a waste product (overflow metabolism), such as the conversion of glucose to lactate (the Warburg Effect) in tumors. Here we report that excess glucose metabolism generates acetate, a key nutrient whose source has been unclear. Conversion of pyruvate, the product of glycolysis, to acetate occurs through two mechanisms: 1) coupling to reactive oxygen species (ROS), and 2) a neomorphic enzyme activity from keto acid dehydrogenases that enable it to function as a pyruvate decarboxylase. Furthermore, we demonstrate that glucose-derived acetate is sufficient to maintain acetyl-coenzyme A (Ac-CoA) pools and cell proliferation in certain limited metabolic environments such as during mitochondrial dysfunction or ATP citrate lyase (ACLY) deficiency. Thus, de novo acetate production is coupled to the activity of central carbon metabolism providing possible regulatory mechanisms and links to pathophysiology.peer-reviewed)

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“…Intracellular metabolites can reflect the physiological state of cells. Hyphenated UPLC-MS is a relatively new technique for the separation of complex samples and shows promise for metabolomics (Bricker et al, 2012;Paglia et al, 2012;Wu et al, 2011). It is a potential technology for the classification of the cells.…”

Section: Analytical Instrument Platformsmentioning

confidence: 99%

Cell Metabolomics

Zhang

Sun²,

Xu³

et al. 2013

OMICS: A Journal of Integrative Biology

166

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Metabolomics technologies enable the examination and identification of endogenous biochemical reaction products, revealing information on the precise metabolic pathways and processes within a living cell. Metabolism is either directly or indirectly involved with every aspect of cell function, and metabolomics is thus believed to be a reflection of the phenotype of any cell. Metabolomics analysis of cells has many potential applications and advantages compared to currently used methods in the postgenomics era. Cell metabolomics is an emerging field that addresses fundamental biological questions and allows one to observe metabolic phenomena in cells. Cell metabolomics consists of four sequential steps: (a) sample preparation and extraction, (b) metabolic profiles of low-weight metabolites based on MS or NMR spectroscopy techniques, (c) pattern recognition approaches and bioinformatics data analysis, (d) metabolites identification resulting in putative biomarkers and molecular targets. The biomarkers are eventually placed in metabolic networks to provide insight on the cellular biochemical phenomena. This article analyzes the recent developments in use of metabolomics to characterize and interpret the cellular metabolome in a wide range of pathophysiological and clinical contexts, and the putative roles of the endogenous small molecule metabolites in this new frontier of postgenomics biology and systems medicine.

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A Mitochondrial Pyruvate Carrier Required for Pyruvate Uptake in Yeast, Drosophila , and Humans

Cited by 776 publications

References 19 publications

Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy

Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy

De novo acetate production is coupled to central carbon metabolism in mammals

Cell Metabolomics

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