INDY—From Flies to Worms, Mice, Rats, Non-Human Primates, and Humans

Abstract

I’m Not Dead Yet (Indy) is a fly homologue of the mammalian SLC13A5 (mSLC13A5) plasma membrane citrate transporter, a key metabolic regulator and energy sensor involved in health, longevity, and disease. Reduction of Indy gene activity in flies, and its homologs in worms, modulates metabolism and extends longevity. The metabolic changes are similar to what is obtained with caloric restriction (dietary restriction). Similar effects on metabolism have been observed in mice and rats. As a citrate transporter, INDY regulates cytoplasmic citrate levels. Indy flies heterozygous for a P-element insertion have increased spontaneous physical activity, increased fecundity, reduced insulin signaling, increased mitochondrial biogenesis, preserved intestinal stem cell homeostasis, lower lipid levels, and increased stress resistance. Mammalian Indy knockout (mIndy-KO) mice have higher sensitivity to insulin signaling, lower blood pressure and heart rate, preserved memory and are protected from the negative effects of a high-fat diet and some of the negative effects of aging. Reducing mIndy expression in human hepatocarcinoma cells has recently been shown to inhibit cell proliferation. Reduced Indy expression in the fly intestine affects intestinal stem cell proliferation, and has recently been shown to also inhibit germ cell proliferation in males with delayed sperm maturation and decreased spermatocyte numbers. These results highlight a new connection between energy metabolism and cell proliferation. The overrall picture in a variety of species points to a conserved role of INDY for metabolism and health. This is illustrated by an association of high mIndy gene expression with non-alcoholic fatty liver disease in obese humans. mIndy (mSLC13A5) coding region mutations (e.g., loss-of-function) are also associated with adverse effects in humans, such as autosomal recessive early infantile epileptic encephalopathy and Kohlschütter−Tönz syndrome. The recent findings illustrate the importance of mIndy gene for human health and disease. Furthermore, recent work on small-molecule regulators of INDY highlights the promise of INDY-based treatments for ameliorating disease and promoting healthy aging.

Targeting Longevity Gene SLC13A5: A Novel Approach to Prevent Age-Related Bone Fragility and Osteoporosis

“…However, signifi-cant species differences in target biology may result in different phenotypes in humans and mice with genetic Slc13a5 deficiencies. In particular, differences in transport kinetics could lead to different outcomes associated with Slc13a5-deficient mice or mutations or other variants in human Slc13a5 [13,50]. The high affinity/low capacity transporter in mice is completely saturated under plasma citrate concentrations of approximately 150-200 µM and cannot respond to further increases in circulating citrate, whereas the human low affinity/high capacity transporter is not saturated, and therefore, can respond to changes in citrate levels [2,51].…”

SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy

“…At physiological concentrations of citrate, 150–200 µM for both mouse and human, the mouse NaCT functions in a saturated manner, whereas the human NaCT does not. This may suggest physiological differences in citrate metabolism between these species and why Slc13a5 knock out (KO) mice have a milder phenotype than SDD patients [ 19 , 20 , 21 ].…”