Knockout of
            <i>Slc25a19</i>
            causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia

Lindhurst, Marjorie J.; Fiermonte, Giuseppe; Song, Shiwei; Struys, Eduard A.; Leonardis, Francesco De; Schwartzberg, Pamela L.; Chen, Amy; Castegna, Alessandra; Verhoeven, Nanda M.; Mathews, Christopher K.; Palmieri, Ferdinando; Biesecker, Leslie G.

doi:10.1073/pnas.0607661103

Cited by 140 publications

(137 citation statements)

References 21 publications

(24 reference statements)

Supporting

Mentioning

135

Contrasting

Order By: Relevance

“…One million wild-type and siUCP2-HepG2 cells were grown in 75-cm 2 flasks for 48 h in the presence of 5 mM glucose or 2 mM glutamine; the medium was collected and centrifuged at 700 × g for 5 min to remove cell debris. Lactate in the supernatants from both cell types was assayed as described before (43).…”

Section: Methodsmentioning

confidence: 99%

UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation

Vozza

Parisi

Leonardis

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

328

346

View full text Add to dashboard Cite

Uncoupling protein 2 (UCP2) is involved in various physiological and pathological processes such as insulin secretion, stem cell differentiation, cancer, and aging. However, its biochemical and physiological function is still under debate. Here we show that UCP2 is a metabolite transporter that regulates substrate oxidation in mitochondria. To shed light on its biochemical role, we first studied the effects of its silencing on the mitochondrial oxidation of glucose and glutamine. Compared with wild-type, UCP2-silenced human hepatocellular carcinoma (HepG2) cells, grown in the presence of glucose, showed a higher inner mitochondrial membrane potential and ATP:ADP ratio associated with a lower lactate release. Opposite results were obtained in the presence of glutamine instead of glucose. UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. The higher levels of citric acid cycle intermediates found in the mitochondria of siUCP2-HepG2 cells compared with those found in wild-type cells in addition to the transport data indicate that, by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. Our work reveals a unique regulatory mechanism in cell bioenergetics and provokes a substantial reconsideration of the physiological and pathological functions ascribed to UCP2 based on its purported uncoupling properties. mitochondrial carrier | glucose and glutamine metabolism | Warburg effect | metabolic reprogramming | diabetes M itochondria couple respiratory oxidation of nutrients to ATP synthesis through an electrochemical proton gradient. Proton leak allows partial uncoupling of oxidative phosphorylation, producing heat. Through this mechanism, Uncoupling protein (UCP)1, a member of the mitochondrial carrier family (MCF), regulates adaptive thermogenesis in mammals. In 1997 a protein similar to UCP1 was cloned and named UCP2 (1) based on the assumption that the sequence homology implied a similar function. Whereas UCP1 has a clear-cut uncoupling activity relevant to nonshivering thermogenesis, this is not the case for UCP2. UCP2 has been involved in numerous physiopathological conditions including metabolic disorders, inflammation, ischemic shock, cancer, and aging. Furthermore, changes in UCP2 expression affect metabolic functions (2, 3). It has been suggested that these metabolic actions of UCP2 are due to a mild UCP1-like uncoupling activity (4, 5) that, combined with the generally low levels of UCP2 expression, would regulate the release of reactive oxygen species (ROS) (6) without significantly affecting energy conservation. Although fatty acid-dependent proton transport mediated by UCP2 was reported in reconstituted liposomes (7), a mounting body of evidence argues against UCP2 having an uncoupling activity in vivo (8, 9) and sugge...

show abstract

Section: Methodsmentioning

confidence: 99%

UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation

Vozza

Parisi

Leonardis

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

328

346

View full text Add to dashboard Cite

show abstract

“…These disorders include PDC deficiency, lipoamide dehydrogenase deficiency, or Amish lethal microcephaly syndromes (3,11,13). It is also worth noting that complete KO mouse models for Pdha1, Dld, Slc25a19, as well as for E4f1, all show severe developmental defects and lethality during early embryonic development (4,22,(37)(38)(39). This finding raises interesting questions about the importance of the E4F1-controlled PDH-program during embryogenesis and beyond, about the poorly characterized metabolic rewiring of the pyruvate pathway that may occur during development.…”

Section: Muscular Defects Of E4f1 Ko(acta) Mice Are Rescued Upon Pharmentioning

confidence: 99%

“…To fuel the PDC, pyruvate translocates across the inner mitochondrial membrane through the heterodimeric pyruvate transporter mitochondrial pyruvate carrier 1 (MPC1)/MPC2 (2,3). The activity of the PDC depends on several cofactors, including lipoate, CoEnzymeA (CoA), FAD+, NAD+, and thiamine pyrophosphate, the latter being imported in the mitochondria by the SLC25A19 transporter (4). So far, finetuning of PDC activity has been mainly attributed to posttranslational modifications of its subunits (5,6), including the extensively studied phosphorylation of PDHA1/E1 modulated by PDH kinases (PDK1-4) and phosphatases (PDP1-2).…”

mentioning

confidence: 99%

E4F1 controls a transcriptional program essential for pyruvate dehydrogenase activity

Lacroix

Rodier

Kirsh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The mitochondrial pyruvate dehydrogenase (PDH) complex (PDC) acts as a central metabolic node that mediates pyruvate oxidation and fuels the tricarboxylic acid cycle to meet energy demand. Here, we reveal another level of regulation of the pyruvate oxidation pathway in mammals implicating the E4 transcription factor 1 (E4F1). E4F1 controls a set of four genes [dihydrolipoamide acetlytransferase (Dlat), dihydrolipoyl dehydrogenase (Dld), mitochondrial pyruvate carrier 1 (Mpc1), and solute carrier family 25 member 19 (Slc25a19)] involved in pyruvate oxidation and reported to be individually mutated in human metabolic syndromes. E4F1 dysfunction results in 80% decrease of PDH activity and alterations of pyruvate metabolism. Genetic inactivation of murine E4f1 in striated muscles results in viable animals that show low muscle PDH activity, severe endurance defects, and chronic lactic acidemia, recapitulating some clinical symptoms described in PDC-deficient patients. These phenotypes were attenuated by pharmacological stimulation of PDH or by a ketogenic diet, two treatments used for PDH deficiencies. Taken together, these data identify E4F1 as a master regulator of the PDC.E4F1 | PDH | pyruvate | muscle | endurance

show abstract

“…TPP is then either used in the cytoplasm or is imported in the mitochondria via a carriermediated process that involves the mitochondrial TPP transporter (encoded by the SLC25A19 gene; see Ref. 19), for utilization in carbohydrate metabolism and energy production. The importance of thiamin for human health and well-being is evident by the range of clinical abnormalities that result from its deficiency, which include cardiovascular and neurological disorders (4,31,35).…”

mentioning

confidence: 99%

Effect of chronic alcohol feeding on physiological and molecular parameters of renal thiamin transport

Subramanian

Subramanya

Tsukamoto

et al. 2010

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Subramanian VS, Subramanya SB, Tsukamoto H, Said HM. Effect of chronic alcohol feeding on physiological and molecular parameters of renal thiamin transport. Am J Physiol Renal Physiol 299: F28-F34, 2010. First published April 28, 2010 doi:10.1152/ajprenal.00140.2010.-The renal thiamin reabsorption process plays an important role in regulating thiamin body homeostasis and involves both thiamin transporters-1 and -2 (THTR1 and THTR2). Chronic alcohol use is associated with thiamin deficiency. Although a variety of factors contribute to the development of this deficiency, effects of chronic alcohol use on renal thiamin transport have not been thoroughly examined. We addressed this issue by examining the effect of chronic alcohol feeding of rats with liquid diet on physiological and molecular parameters of renal thiamin transport. Chronic alcohol feeding caused a significant inhibition in carrier-mediated thiamin transport across the renal brushborder membrane and was evident as early as 2 wk after initiation of alcohol feeding. Similarly, thiamin transport across the renal basolateral membrane was significantly inhibited by chronic alcohol feeding. The inhibition in renal thiamin transport was associated with a marked decrease in the level of expression of THTR1 and -2 proteins, mRNAs, and heterogeneous nuclear RNAs. Chronic alcohol feeding also caused a significant reduction in the level of expression of thiamin pyrophosphokinase but not that of the mitochondrial thiamin pyrophosphate transporter. These studies show that chronic alcohol feeding inhibits the entry and exit of thiamin in the polarized renal epithelial cells and that the effect is, at least in part, mediated at the transcriptional level. These findings also suggest that chronic alcohol feeding interferes with the normal homeostasis of thiamin in renal epithelial cells.transporter; vitamin B1; kidney; thiamin transporter-1; thiamin transporter-2 THIAMIN, A WATER-SOLUBLE vitamin, is essential for cellular function, growth, and development. The vitamin is enzymatically converted into its active form, thiamin pyrophosphate (TPP), in the cytoplasm via the action of thiamin pyrophosphokinase (TPKase), a rate-limiting enzyme that plays an important role in regulating cellular thiamin homeostasis. While all mammalian nucleated cells possess the ability to convert thiamin to TPP, the liver and kidneys are especially active in this regard (10,22,36). TPP is then either used in the cytoplasm or is imported in the mitochondria via a carriermediated process that involves the mitochondrial TPP transporter (encoded by the SLC25A19 gene; see Ref. 19), for utilization in carbohydrate metabolism and energy production. The importance of thiamin for human health and well-being is evident by the range of clinical abnormalities that result from its deficiency, which include cardiovascular and neurological disorders (4, 31, 35). Beriberi and the Wernicke-Korsakoff syndrome are well-known thiamin deficiency diseases (24, 35).All mammals cannot synthesize thiamin; thus, the...

show abstract

Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia

Cited by 140 publications

References 21 publications

UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation

UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation

E4F1 controls a transcriptional program essential for pyruvate dehydrogenase activity

Effect of chronic alcohol feeding on physiological and molecular parameters of renal thiamin transport

Contact Info

Product

Resources

About