Abstract
I’m Not Dead Yet (Indy) is a fly gene that encodes a homologue of mammalian SLC13A5 plasma membrane citrate transporter. Reducing expression of Indy gene in flies, and its homologues in worms, extends longevity. Indy reduction in flies, worms, mice and rats affects metabolism by regulating the levels of cytoplasmic citrate, inducing a state similar to calorie restriction. Changes include lower lipid levels, increased insulin sensitivity, increased mitochondrial biogenesis, and prevention of weight gain, among others. The INDY protein is predominantly expressed in fly metabolic tissues: the midgut, fat body and oenocytes. Changes in fly midgut metabolism associated with reduced Indy gene activity lead to preserved mitochondrial function and reduced production of reactive oxygen species. All these changes lead to preserved intestinal stem cell homeostasis, which has a key role in maintaining intestinal epithelium function and enhancing fly healthspan and lifespan. Indy gene expression levels change in response to caloric content of the diet, inflammation and aging, suggesting that INDY regulates metabolic adaptation to nutrition or energetic requirements by controlling citrate levels.
Highlights
I’m not dead yet (Indy) is a fly homologue of mammalian SLC13A5 plasma membrane transporter with highest affinity for transporting the metabolite citrate, which is a critical regulator of metabolism [1,2,3]
By regulating cytoplasmic citrate levels, INDY acts as a metabolic regulator in modulating glucose and lipid levels, and energy production in mitochondria [44,81]
Metabolic changes associated with Indy reduction in the fly midgut results in dramatic changes in midgut physiology that lead to preserved intestinal intestinal stem cell (ISC) homeostasis
Summary
I’m not dead yet (Indy) is a fly homologue of mammalian SLC13A5 plasma membrane transporter with highest affinity for transporting the metabolite citrate, which is a critical regulator of metabolism [1,2,3]. Citrate is a key metabolite in the tricarboxylic acid (TCA) cycle and has a highly conserved role in glucose, lipid, and energy metabolism across species This is illustrated by studies that show similar effects of Indy reduction on metabolism in flies, worms, mice, rats, non-human primates and humans [10,11,12]. Reducing Indy gene expression levels extends longevity in flies and worms by affecting multiple metabolic pathways [1,10,13,14,15,16,17]. Flies with reduced Indy levels have several metabolic and physiological phenotypes parallel to CR [30,31] These changes include increased mitochondrial biogenesis, increased spontaneous physical activity, increased resistance to stress, reduced reactive oxygen species (ROS) production, smaller body weight and reduced insulin/insulin-like growth factor signaling (IIS), among others [16,22,23,32]. Identification of similar phenotypes and changes associated with reduced INDY levels in multiple organisms suggests a highly conserved role of INDY in metabolism
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