Abstract
The Drosophila Indy (I'm Not Dead Yet) gene encodes a plasma membrane transporter of Krebs cycle intermediates, with robust expression in tissues associated with metabolism. Reduced INDY alters metabolism and extends longevity in a manner similar to caloric restriction (CR); however, little is known about the tissue specific physiological effects of INDY reduction. Here we focused on the effects of INDY reduction in the Drosophila midgut due to the importance of intestinal tissue homeostasis in healthy aging and longevity. The expression of Indy mRNA in the midgut changes in response to aging and nutrition. Genetic reduction of Indy expression increases midgut expression of the mitochondrial regulator spargel/dPGC-1, which is accompanied by increased mitochondrial biogenesis and reduced reactive oxygen species (ROS). These physiological changes in the Indy mutant midgut preserve intestinal stem cell (ISC) homeostasis and are associated with healthy aging. Genetic studies confirm that dPGC-1 mediates the regulatory effects of INDY, as illustrated by lack of longevity extension and ISC homeostasis in flies with mutations in both Indy and dPGC1. Our data suggest INDY may be a physiological regulator that modulates intermediary metabolism in response to changes in nutrient availability and organismal needs by modulating dPGC-1.
Highlights
Caloric restriction (CR) extends lifespan in most species and promotes organismal energy balance by affecting intermediary metabolism and mitochondrial biogenesis [1,2,3,4]
Exposure to 20 mM paraquat, an agent known to induce free radical production and mimic aging, upregulates Indy mRNA and protein levels in young control flies to levels similar to those that are observed in aged flies (Fig. 1B, S1B, S1C) [5, 19]
To investigate the relationship between Indy mRNA and nutrient availability in the midgut, we measured Indy mRNA levels in female yw control, Indy206/+ and Indy206/Indy206 flies on a normal, high caloric (HC) and CR diets at 20 days
Summary
Caloric restriction (CR) extends lifespan in most species and promotes organismal energy balance by affecting intermediary metabolism and mitochondrial biogenesis [1,2,3,4]. Interventions that alter intermediary metabolism are though to extend longevity by preserving the balance between energy production and free radical production [1, 5, 6]. DPGC-1/spargel is the Drosophila homolog of mammalian PGC-1, a transcriptional co-activator that promotes mitochondrial biogenesis by increasing the expression of genes encoding mitochondrial proteins [15, 16]. Previous analyses of Indy mutant flies revealed upregulation of mitochondrial biogenesis mediated by increased levels of dPGC-1 in heads and thoraces [6].
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