Indy Mutations and Drosophila Longevity

Blanka Rogina,Stephen L Helfand

doi:10.3389/fgene.2013.00047

Blanka Rogina, Stephen L Helfand

Open Access

https://doi.org/10.3389/fgene.2013.00047

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Abstract

Decreased expression of the fly and worm Indy genes extends longevity. The fly Indy gene and its mammalian homolog are transporters of Krebs cycle intermediates, with the highest rate of uptake for citrate. Cytosolic citrate has a role in energy regulation by affecting fatty acid synthesis and glycolysis. Fly, worm, and mice Indy gene homologs are predominantly expressed in places important for intermediary metabolism. Consequently, decreased expression of Indy in fly and worm, and the removal of mIndy in mice exhibit changes associated with calorie restriction, such as decreased levels of lipids, changes in carbohydrate metabolism and increased mitochondrial biogenesis. Here we report that several Indy alleles in a diverse array of genetic backgrounds confer increased longevity.

Highlights

Aging is a complex process that can be modulated by environment and affected by genetic manipulations, such as single gene mutations
MUTATION IN Indy206 EXTENDS LIFE SPAN IN DIFFERENT GENETIC BACKGROUNDS In order to further examine if genetic background may contribute to the life span extension of heterozygous Indy mutant flies, we determined the survivorship of Indy heterozygous mutant flies in Hyperkinetic1 (Hk1) and long- and short-lived selected Luckinbill lines (Figures 1A-E) (Kaplan and Trout, 1969; Luckinbill and Clare, 1985)
The 2216 and 1085 lines that were derived from the same mutagenesis as Indy206, but do not have a P-element insertions in the Indy region were used as control in Rogina et al, 2000

Summary

Introduction

Aging is a complex process that can be modulated by environment and affected by genetic manipulations, such as single gene mutations. Mutations in the Indy (I’m Not Dead Yet ) gene extend life span of the fruit fly, Drosophila melanogaster (Rogina et al, 2000; Wang et al, 2009). Indy encodes the fly homolog of a mammalian di and tricarboxylate transporter involved in reabsorbing Krebs cycle intermediates, such as citrate, pyruvate, and α-ketoglutarate (Knauf et al, 2002, 2006; Pajor, 2006). Functional characterization of the transporter encoded by the Indy structural gene confirmed that it is a transporter of Krebs cycle intermediates (Inoue et al, 2002; Knauf et al, 2002). Further studies have shown that INDY functions as an anion exchanger of dicarboxylate and tricarboxylate Krebs cycle intermediates (Knauf et al, 2006). Crystal structure of a bacterial INDY homolog from Vibrio cholera (VcINDY) reveals that one citrate and one sodium molecule is bound per protein but the mature transporter is likely found in the form of a dimer (Mancusso et al, 2012)

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