Uncoupling protein-2 contributes significantly to high mitochondrial proton leak in INS-1E insulinoma cells and attenuates glucose-stimulated insulin secretion
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Proton leak exerts stronger control over ATP/ADP in mitochondria from clonal pancreatic β-cells (INS-1E) than in those from rat skeletal muscle, due to the higher proton conductance of INS-1E mitochondria [Affourtit and Brand (2006) Biochem. J. 393, 151–159]. In the present study, we demonstrate that high proton leak manifests itself at the cellular level too: the leak rate (measured as myxothiazol-sensitive, oligomycin-resistant respiration) was nearly four times higher in INS-1E cells than in myoblasts. This relatively high leak activity was decreased more than 30% upon knock-down of UCP2 (uncoupling protein-2) by RNAi (RNA interference). The high contribution of UCP2 to leak suggests that proton conductance through UCP2 accounts for approx. 20% of INS-1E respiration. UCP2 knock-down enhanced GSIS (glucose-stimulated insulin secretion), consistent with a role for UCP2 in β-cell physiology. We propose that the high mitochondrial proton leak in β-cells is a mechanism which amplifies the effect of physiological UCP2 regulators on cytoplasmic ATP/ADP and hence on insulin secretion.
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Approximately 20% of proton leak in beta-cells is thought to occur due to presence of UCP2.
“Approximately 20% of the proton leak in beta-cells is thought to occur due to the presence of UCP2 .178,179”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [178]
UCP2 is a protein present in the beta-cell mitochondria inner membrane, postulated to dampen GSIS by dissipating mitochondrial proton motive force as heat, reducing efficiency of ATP production.
“UCP2 is a protein present in the beta-cell mitochondria inner membrane, which was postulated to dampen GSIS by dissipating mitochondrial proton motive force as heat (due to its analogy with UCP1), thereby reducing the efficiency of ATP production.”
From A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives (2021) · cites this paper as [178]
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Self-citation
- Authors
- Affourtit, C., & Brand, M. D.
- Affiliations
- MRC Mitochondrial Biology Unit (GB)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2007-12-11
- Volume
- 409
- Issue
- 1
- Pages
- 199-204
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2127791120
- Cited by
- 85
- References
- 25
- Citations by year
- 2024: 3 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 5 · 2017: 2 · 2016: 5 · 2015: 6 · 2014: 5 · 2013: 8 · 2012: 10
- FWCI
- 6.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion, other-oa)
- Funders
- Medical Research Council
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- UCP2, mitochondrial proton leak, INS-1E cells, insulinoma, glucose-stimulated insulin secretion, pancreatic beta cells, ATP/ADP ratio, mitochondrial respiration, RNA knockdown, oligomycin resistance
- MeSH terms
- Uncoupling Protein 2, Insulin Secretion, Animals, Cytoplasm, Glucose, Insulin, Ion Channels, Membrane Potentials, Methacrylates, Mitochondria, Oligomycins, Oxygen, Oxygen Consumption, Phosphorylation, Thiazoles, Mitochondrial Proteins, RNA Interference, Insulin-Secreting Cells, Rats
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