Functional characterization and immunolocalization of the transporter encoded by the life-extending gene Indy.
Caloric restriction extends life span in a variety of species, highlighting the importance of energy balance in aging. A new longevity gene, Indy (for I'm not dead yet), which doubles the average life span of flies without a loss of fertility or physical activity, was postulated to extend life by affecting intermediary metabolism. We report that functional studies in Xenopus oocytes show INDY is a metabolite transporter that mediates the high-affinity, disulfonic stilbene-sensitive flux of dicarboxylates and citrate across the plasma membrane by a mechanism that is not coupled to Na(+), K(+), or Cl(-). Immunocytochemical studies localize INDY to the plasma membrane with most prominent expression in adult fat body, oenocytes, and the basolateral region of midgut cells and show that life-extending mutations in Indy reduce INDY expression. We conclude that INDY functions as a novel sodium-independent mechanism for transporting Krebs and citric acid cycle intermediates through the epithelium of the gut and across the plasma membranes of organs involved in intermediary metabolism and storage. The life-extending effect of mutations in Indy is likely caused by an alteration in energy balance caused by a decrease in INDY transport function.
Knauf
Felix
F
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Rogina
Blanka
B
Jiang
Zhirong
Z
Aronson
Peter S
PS
Helfand
Stephen L
SL
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002412:Cations; D002462:Cell Membrane / Q000378:metabolism; D002951:Citrates / Q000378:metabolism; D002952:Citric Acid Cycle; D029382:Dicarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005665:Furosemide / Q000494:pharmacology; D017344:Genes, Insect; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010693:Phloretin / Q000494:pharmacology; D019802:Succinic Acid / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus
D002412:Cations; D002951:Citrates; D029382:Dicarboxylic Acid Transporters; D029721:Drosophila Proteins; C417606:Indy protein, Drosophila; D027981:Symporters; D005665:Furosemide; D019802:Succinic Acid; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D010693:Phloretin