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The life-extending gene Indy encodes an exchanger for Krebs-cycle intermediates.
Knauf F
,
Mohebbi N
,
Teichert C
,
Herold D
,
Rogina B
,
Helfand S
,
Gollasch M
,
Luft FC
,
Aronson PS
.
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A longevity gene called Indy (for 'I'm not dead yet'), with similarity to mammalian genes encoding sodium-dicarboxylate cotransporters, was identified in Drosophila melanogaster. Functional studies in Xenopus oocytes showed that INDY mediates the flux of dicarboxylates and citrate across the plasma membrane, but the specific transport mechanism mediated by INDY was not identified. To test whether INDY functions as an anion exchanger, we examined whether substrate efflux is stimulated by transportable substrates added to the external medium. Efflux of [14C]citrate from INDY-expressing oocytes was greatly accelerated by the addition of succinate to the external medium, indicating citrate-succinate exchange. The succinate-stimulated [14C]citrate efflux was sensitive to inhibition by DIDS (4,4'-di-isothiocyano-2,2'-disulphonic stilbene), as demonstrated previously for INDY-mediated succinate uptake. INDY-mediated efflux of [14C]citrate was also stimulated by external citrate and oxaloacetate, indicating citrate-citrate and citrate-oxaloacetate exchange. Similarly, efflux of [14C]succinate from INDY-expressing oocytes was stimulated by external citrate, alpha-oxoglutarate and fumarate, indicating succinate-citrate, succinate-alpha-oxoglutarate and succinate-fumarate exchange respectively. Conversely, when INDY-expressing Xenopus oocytes were loaded with succinate and citrate, [14C]succinate uptake was markedly stimulated, confirming succinate-succinate and succinate-citrate exchange. Exchange of internal anion for external citrate was markedly pH(o)-dependent, consistent with the concept that citrate is co-transported with a proton. Anion exchange was sodium-independent. We conclude that INDY functions as an exchanger of dicarboxylate and tricarboxylate Krebs-cycle intermediates. The effect of decreasing INDY activity, as in the long-lived Indy mutants, may be to alter energy metabolism in a manner that favours lifespan extension.
Burckhardt,
Transport of organic anions across the basolateral membrane of proximal tubule cells.
2003, Pubmed
Burckhardt,
Transport of organic anions across the basolateral membrane of proximal tubule cells.
2003,
Pubmed
Burckhardt,
The renal Na(+)-dependent dicarboxylate transporter, NaDC-3, translocates dimethyl- and disulfhydryl-compounds and contributes to renal heavy metal detoxification.
2002,
Pubmed
,
Xenbase
Edwards,
alpha-Ketoglutarate transport in rat renal brush-border and basolateral membrane vesicles.
1997,
Pubmed
Fei,
Structural and functional characteristics of two sodium-coupled dicarboxylate transporters (ceNaDC1 and ceNaDC2) from Caenorhabditis elegans and their relevance to life span.
2003,
Pubmed
Fei,
Relevance of NAC-2, an Na+-coupled citrate transporter, to life span, body size and fat content in Caenorhabditis elegans.
2004,
Pubmed
,
Xenbase
Inoue,
Functional identity of Drosophila melanogaster Indy as a cation-independent, electroneutral transporter for tricarboxylic acid-cycle intermediates.
2002,
Pubmed
,
Xenbase
Kaplan,
The mitochondrial tricarboxylate transport protein. cDNA cloning, primary structure, and comparison with other mitochondrial transport proteins.
1993,
Pubmed
Kaplan,
Structure and function of mitochondrial anion transport proteins.
2001,
Pubmed
Klingenberg,
Kinetic study of the tricarboxylate carrier in rat liver mitochondria.
1972,
Pubmed
Knauf,
Identification of a chloride-formate exchanger expressed on the brush border membrane of renal proximal tubule cells.
2001,
Pubmed
,
Xenbase
Knauf,
Functional characterization and immunolocalization of the transporter encoded by the life-extending gene Indy.
2002,
Pubmed
,
Xenbase
Koubova,
How does calorie restriction work?
2003,
Pubmed
Lin,
Extended life-span and stress resistance in the Drosophila mutant methuselah.
1998,
Pubmed
Marden,
Conditional tradeoffs between aging and organismal performance of Indy long-lived mutant flies.
2003,
Pubmed
Pajor,
Molecular cloning, chromosomal organization, and functional characterization of a sodium-dicarboxylate cotransporter from mouse kidney.
2000,
Pubmed
,
Xenbase
Pajor,
Sodium-coupled transporters for Krebs cycle intermediates.
1999,
Pubmed
,
Xenbase
Rogina,
Extended life-span conferred by cotransporter gene mutations in Drosophila.
2000,
Pubmed
Stewart,
Regulation of AE2 anion exchanger by intracellular pH: critical regions of the NH(2)-terminal cytoplasmic domain.
2001,
Pubmed
,
Xenbase
Tatar,
Chaperoning extended life.
1997,
Pubmed
Watson,
Citrate and the conversion of carbohydrate into fat. Fatty acid synthesis by a combination of cytoplasm and mitochondria.
1970,
Pubmed
