The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis

Kannan, Kavitha; Rogina, Blanka

doi:10.3390/metabo11100705

Cited by 8 publications

(6 citation statements)

References 89 publications

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“…Studies have shown that impaired citrate transport leads to low cytosolic citrate levels and thus, plausibly decreases the rate of fatty acid and lipid synthesis [40]. This hypothesis is consistent with our findings in the brain, where relative levels of lipids and fatty acids were low.…”

Section: Discussionsupporting

confidence: 92%

Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis

Milosavljevic

Glinton

et al. 2022

Metabolites

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Though biallelic variants in SLC13A5 are known to cause severe encephalopathy, the mechanism of this disease is poorly understood. SLC13A5 protein deficiency reduces citrate transport into the cell. Downstream abnormalities in fatty acid synthesis and energy generation have been described, though biochemical signs of these perturbations are inconsistent across SLC13A5 deficiency patients. To investigate SLC13A5-related disorders, we performed untargeted metabolic analyses on the liver, brain, and serum from a Slc13a5-deficient mouse model. Metabolomic data were analyzed using the connect-the-dots (CTD) methodology and were compared to plasma and CSF metabolomics from SLC13A5-deficient patients. Mice homozygous for the Slc13a5tm1b/tm1b null allele had perturbations in fatty acids, bile acids, and energy metabolites in all tissues examined. Further analyses demonstrated that for several of these molecules, the ratio of their relative tissue concentrations differed widely in the knockout mouse, suggesting that deficiency of Slc13a5 impacts the biosynthesis and flux of metabolites between tissues. Similar findings were observed in patient biofluids, indicating altered transport and/or flux of molecules involved in energy, fatty acid, nucleotide, and bile acid metabolism. Deficiency of SLC13A5 likely causes a broader state of metabolic dysregulation than previously recognized, particularly regarding lipid synthesis, storage, and metabolism, supporting SLC13A5 deficiency as a lipid disorder.

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Section: Discussionsupporting

confidence: 92%

Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis

Milosavljevic

Glinton

et al. 2022

Metabolites

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“…Citrate synthase catalyzes the formation of citrate from acetyl-CoA and oxaloacetate in the TCA cycle. Decreased citrate levels can have various downstream effects on cellular metabolism, including altered lipid metabolism and impaired gluconeogenesis [180,181]. CS has also been implicated in mitochondrial dynamic processes such as fusion and fission [182].…”

Section: Discussionmentioning

confidence: 99%

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process

Maudsley

Schrauwen

Harputluoğlu

et al. 2023

IJMS

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G protein-coupled receptors (GPCRs) play a significant role in controlling biological paradigms such as aging and aging-related disease. We have previously identified receptor signaling systems that are specifically associated with controlling molecular pathologies associated with the aging process. Here, we have identified a pseudo-orphan GPCR, G protein-coupled receptor 19 (GPR19), that is sensitive to many molecular aspects of the aging process. Through an in-depth molecular investigation process that involved proteomic, molecular biological, and advanced informatic experimentation, this study found that the functionality of GPR19 is specifically linked to sensory, protective, and remedial signaling systems associated with aging-related pathology. This study suggests that the activity of this receptor may play a role in mitigating the effects of aging-related pathology by promoting protective and remedial signaling systems. GPR19 expression variation demonstrates variability in the molecular activity in this larger process. At low expression levels in HEK293 cells, GPR19 expression regulates signaling paradigms linked with stress responses and metabolic responses to these. At higher expression levels, GPR19 expression co-regulates systems involved in sensing and repairing DNA damage, while at the highest levels of GPR19 expression, a functional link to processes of cellular senescence is seen. In this manner, GPR19 may function as a coordinator of aging-associated metabolic dysfunction, stress response, DNA integrity management, and eventual senescence.

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“…It would be of interest to examine the role of mINDY in testes of mice, rats and humans, though mINDY is expressed at low levels in mammalian testis ( Inoue, et al, 2002a ; von Loeffelholz et al, 2017 ). In contrast, Indy 206 /+ and Indy 302 /+ female flies have increased fecundity compared to controls suggesting sex-specific differences with Indy reduction in flies ( Rogina et al, 2000 ; Marden et al, 2003 ; Kannan and Rogina, 2021 ). Similar increases in female fecundity were observed in natural populations of flies containing the Hoppel transposable element in the Indy region ( Zhu et al, 2014 ).…”

Section: Introductionmentioning

confidence: 90%

“…INDY reduction also leads to increased levels of antioxidant genes. These physiological changes delay age-associated increases in the ISC proliferation rate, leading to preserved ISC homeostasis ( Rogers and Rogina 2014 ; Rogers and Rogina 2015 ; Kannan and Rogina 2021 ). Altogether, these data indicate that Indy /INDY expression levels are key for cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis

Cited by 8 publications

References 89 publications

Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis

Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process

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

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