UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation
Open accessAbstract
Significance: Mitochondrial carriers constitute a large family of transport proteins that play important roles in the intracellular translocation of metabolites, nucleotides, and coenzymes. Despite considerable research efforts, the biochemical function of Uncoupling protein 2 (UCP2), a member of the mitochondrial carrier family reported to be involved in numerous pathologies, is still elusive. Here we show that UCP2 catalyzes an exchange of malate, oxaloacetate, and aspartate for phosphate, and that it exports C4 metabolites from mitochondria to the cytosol in vivo. Our findings also provide evidence that UCP2 activity limits mitochondrial oxidation of glucose and enhances glutaminolysis. These results provide a unique regulatory mechanism in cell bioenergetics and explain the significance of UCP2 levels in metabolic reprogramming occurring under various physiopathological conditions.
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UCP2 may not be an uncoupling protein despite analogy with UCP1, but likely functions as a carbon skeleton exporter from mitochondrial matrix.
“It has been postulated that UCP2 may not be an uncoupling protein despite its analogy with UCP1, but it likely functions as a carbon skeleton exporter from the mitochondrial matrix, and there is experimental evidence for this.188”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [188]
UCP2 exports malate and oxaloacetate from mitochondria into the cytosol thus limiting the entry of pyruvate into the TCA cycle.
“UCP2 exports malate and oxaloacetate from mitochondria into the cytosol thus limiting the entry of pyruvate into the TCA cycle (Vozza et al., 2014).”
From Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation (2016) · cites this paper as Vozza et al., 2014
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“Distinct from UCP1, which uncouples ATP synthesis from the proton gradient by transporting protons into the mitochondrial matrix, UCP2 exports malate and oxaloacetate from mitochondria into the cytosol thus limiting the entry of pyruvate into the TCA cycle (Vozza et al., 2014).”
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- Authors
- 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.
- Affiliations
- Department of Biosciences, Biotechnologies, and Biopharmaceutics and
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IT)
- Centre National de la Recherche Scientifique (FR)
- University of Bari Aldo Moro (IT)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-01-06
- Volume
- 111
- Issue
- 3
- Pages
- 960-965
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3903233
- OpenAlex
- W1988627015
- Cited by
- 407
- References
- 49
- Citations by year
- 2026: 20 · 2025: 28 · 2024: 28 · 2023: 40 · 2022: 34 · 2021: 37 · 2020: 30 · 2019: 34 · 2018: 33 · 2017: 34 · 2016: 36 · 2015: 36 · 2014: 17
- FWCI
- 16.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Regione Puglia
- Ministero dell'Università e della Ricerca (RBRN07BMCT_009)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- UCP2, metabolite transport, glutaminolysis, glutamine oxidation, oxaloacetate, aspartic acid, citric acid cycle intermediates, mitochondrial membrane potential, ATP/ADP ratio, lactate release, hepatocellular carcinoma, cell bioenergetics, lipid vesicles
- MeSH terms
- Uncoupling Protein 2, Carbon, Catalysis, Citric Acid Cycle, Energy Metabolism, Glucose, Glutamine, Humans, Ion Channels, Liposomes, Mitochondria, Oxygen, Oxygen Consumption, Phosphates, Cell Respiration, Gene Silencing, Mitochondrial Proteins, Membrane Potential, Mitochondrial, Hep G2 Cells, HEK293 Cells, Oxaloacetic Acid
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