ArticleProceedings of the National Academy of Sciences of the United States of America2014
UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 243 papers.
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Who cites it
243 citing papers in PubMed, 398 citations in OpenAlex.
- Positive Effects of a Mediterranean Diet Supplemented with Almonds on Female Adipose Tissue Biology in Severe Obesity.Nutrients · 2022Trial
- N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase.bioRxiv : the preprint server for biology · 2026Article
- Reduced Cerebral Infarct Volume in Young UCP2Cells · 2026Article
- Retention and tissue-specific expression of uncoupling protein homoeologs in Xenopus laevis.Biology open · 2026Article
- Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.Biomolecules · 2026Review
- Pro- and Anti-Inflammatory Macrophages Adjust UCP2 Protein Levels Based on Their Intrinsic Metabolism and Available Metabolites.European journal of immunology · 2026Article
- A Structural Context for the Mechanisms of Uncoupling Protein 1 in Brown Fat Thermogenesis.Acta physiologica (Oxford, England) · 2026Review
- From the cytosol to the inner membrane: biogenesis of the mitochondrial carrier family.Protein science : a publication of the Protein Society · 2026Review
- HuR-driven reversible mitochondrial shuttling buffers cytosolic miRNA levels in hepatic cells.The Journal of biological chemistry · 2026Article
- Acylcarnitines in Cancer Metabolism: Mechanistic Insights and Stratification Potential.Cancers · 2026Review
- The Dual Anaplerotic Model (DAM): Integral Roles of Pyruvate Carboxylase and the GABA Shunt in Beta Cell Insulin Secretion.Life (Basel, Switzerland) · 2026Article
- The integrated theory of carcinogenesis: cancer as dysregulated persistence under chronic systemic stress.Frontiers in oncology · 2026Article
- UCP2 Identifies Immunosuppressive Tumor-Associated Macrophages and Is Associated with Predicted Immunotherapy Resistance in Glioma.Oncology research · 2026Article
- Flavoromics approach reveals the dynamic changes of non-volatile and volatile compounds in theFrontiers in nutrition · 2026Article
- Context-dependent roles of UCP2 in cancer: functional heterogeneity, molecular mechanisms and translational perspectives.Frontiers in oncology · 2026Review
- SLC25A mitochondrial carriers as biomarkers and therapeutic targets of spaceflight-induced dysfunction: the ADP/ATP carrier (AAC3) as a structural case study.Journal of translational medicine · 2025Article
- Review
- Generation and transcriptome profiling of bonobo induced pluripotent stem cells using stealth RNA vectors: a tripartite comparative study with humans and chimpanzees.BMC genomics · 2025Article
- β-Cell Mitochondrial Dysfunction: Underlying Mechanisms and Potential Therapeutic Strategies.Cells · 2025Review
- Alteration of metabolic activity regulates mitochondrial temperature in diagnosis in HepG2 hepatocellular carcinoma cells.Scientific reports · 2025Article
183 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.