	RHEA:32823	RHEA:32824	RHEA:32825	RHEA:32826
Reaction direction	undefined	left-to-right	right-to-left	bidirectional
UniProtKB ^help_outline	19 proteins
Gene Ontology ^help_outline	GO:0015114

Publications

Dual and Direction-Selective Mechanisms of Phosphate Transport by the Vesicular Glutamate Transporter.

Preobraschenski J., Cheret C., Ganzella M., Zander J.F., Richter K., Schenck S., Jahn R., Ahnert-Hilger G.

Vesicular glutamate transporters (VGLUTs) fill synaptic vesicles with glutamate and are thus essential for glutamatergic neurotransmission. However, VGLUTs were originally discovered as members of a transporter subfamily specific for inorganic phosphate (Pi). It is still unclear how VGL ... >> More

Vesicular glutamate transporters (VGLUTs) fill synaptic vesicles with glutamate and are thus essential for glutamatergic neurotransmission. However, VGLUTs were originally discovered as members of a transporter subfamily specific for inorganic phosphate (Pi). It is still unclear how VGLUTs accommodate glutamate transport coupled to an electrochemical proton gradient ΔμH+ with inversely directed Pi transport coupled to the Na+ gradient and the membrane potential. Using both functional reconstitution and heterologous expression, we show that VGLUT transports glutamate and Pi using a single substrate binding site but different coupling to cation gradients. When facing the cytoplasm, both ions are transported into synaptic vesicles in a ΔμH+-dependent fashion, with glutamate preferred over Pi. When facing the extracellular space, Pi is transported in a Na+-coupled manner, with glutamate competing for binding but at lower affinity. We conclude that VGLUTs have dual functions in both vesicle transmitter loading and Pi homeostasis within glutamatergic neurons. << Less

Cell Rep. 23:535-545(2018) [PubMed] [EuropePMC]

This publication is cited by 2 other entries.
UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation.

Vozza A., Parisi G., De Leonardis F., Lasorsa F.M., Castegna A., Amorese D., Marmo R., Calcagnile V.M., Palmieri L., Ricquier D., Paradies E., Scarcia P., Palmieri F., Bouillaud F., Fiermonte G.

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 re ... >> More

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. << Less

Proc. Natl. Acad. Sci. U.S.A. 111:960-965(2014) [PubMed] [EuropePMC]

This publication is cited by 7 other entries.

	RHEA:32823	RHEA:32824	RHEA:32825	RHEA:32826
Reaction direction	undefined	left-to-right	right-to-left	bidirectional
UniProtKB ^help_outline	19 proteins
Gene Ontology ^help_outline	GO:0015114

Publications

Dual and Direction-Selective Mechanisms of Phosphate Transport by the Vesicular Glutamate Transporter.

Preobraschenski J., Cheret C., Ganzella M., Zander J.F., Richter K., Schenck S., Jahn R., Ahnert-Hilger G.

Vesicular glutamate transporters (VGLUTs) fill synaptic vesicles with glutamate and are thus essential for glutamatergic neurotransmission. However, VGLUTs were originally discovered as members of a transporter subfamily specific for inorganic phosphate (Pi). It is still unclear how VGL ... >> More

Vesicular glutamate transporters (VGLUTs) fill synaptic vesicles with glutamate and are thus essential for glutamatergic neurotransmission. However, VGLUTs were originally discovered as members of a transporter subfamily specific for inorganic phosphate (Pi). It is still unclear how VGLUTs accommodate glutamate transport coupled to an electrochemical proton gradient ΔμH+ with inversely directed Pi transport coupled to the Na+ gradient and the membrane potential. Using both functional reconstitution and heterologous expression, we show that VGLUT transports glutamate and Pi using a single substrate binding site but different coupling to cation gradients. When facing the cytoplasm, both ions are transported into synaptic vesicles in a ΔμH+-dependent fashion, with glutamate preferred over Pi. When facing the extracellular space, Pi is transported in a Na+-coupled manner, with glutamate competing for binding but at lower affinity. We conclude that VGLUTs have dual functions in both vesicle transmitter loading and Pi homeostasis within glutamatergic neurons. << Less

Cell Rep. 23:535-545(2018) [PubMed] [EuropePMC]

This publication is cited by 2 other entries.
UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation.

Vozza A., Parisi G., De Leonardis F., Lasorsa F.M., Castegna A., Amorese D., Marmo R., Calcagnile V.M., Palmieri L., Ricquier D., Paradies E., Scarcia P., Palmieri F., Bouillaud F., Fiermonte G.

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 re ... >> More

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. << Less

Proc. Natl. Acad. Sci. U.S.A. 111:960-965(2014) [PubMed] [EuropePMC]

This publication is cited by 7 other entries.

Cross-references

Publications

Dual and Direction-Selective Mechanisms of Phosphate Transport by the Vesicular Glutamate Transporter.

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

Cross-references

Publications

Dual and Direction-Selective Mechanisms of Phosphate Transport by the Vesicular Glutamate Transporter.

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