Mitochondrial uncoupling protein 2 in pancreatic β-cells
Pancreatic β-cells have remarkable bioenergetics in which increased glucose supply upregulates the cytosolic ATP/ADP ratio and increases insulin secretion. This arrangement allows glucose-stimulated insulin secretion (GSIS) to be regulated by the coupling efficiency of oxidative phosphorylation. Unc...
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| Veröffentlicht in: | Diabetes, obesity & metabolism obesity & metabolism, 2010-10, Vol.12 (s2), p.134-140 |
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| description | Pancreatic β-cells have remarkable bioenergetics in which increased glucose supply upregulates the cytosolic ATP/ADP ratio and increases insulin secretion. This arrangement allows glucose-stimulated insulin secretion (GSIS) to be regulated by the coupling efficiency of oxidative phosphorylation. Uncoupling protein 2 (UCP2) modulates coupling efficiency and may regulate GSIS. Initial measurements of GSIS and glucose tolerance in Ucp2⁻/⁻ mice supported this model, but recent studies show confounding effects of genetic background. Importantly, however, the enhancement of GSIS is robustly recapitulated with acute UCP2 knockdown in INS-1E insulinoma cells. UCP2 protein level in these cells is dynamically regulated, over at least a fourfold concentration range, by rapid proteolysis (half-life less than 1 h) opposing regulated gene transcription and mRNA translation. Degradation is catalysed by the cytosolic proteasome in an unprecedented pathway that is currently known to act only on UCP2 and UCP3. Evidence for proteasomal turnover of UCP2 includes sensitivity of degradation to classic proteasome inhibitors in cells, and reconstitution of degradation in vitro in mitochondria incubated with ubiquitin and the cytosolic 26S proteasome. These dynamic changes in UCP2 content may provide a fine level of control over GSIS in β-cells. |
| doi_str_mv | 10.1111/j.1463-1326.2010.01264.x |
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This arrangement allows glucose-stimulated insulin secretion (GSIS) to be regulated by the coupling efficiency of oxidative phosphorylation. Uncoupling protein 2 (UCP2) modulates coupling efficiency and may regulate GSIS. Initial measurements of GSIS and glucose tolerance in Ucp2⁻/⁻ mice supported this model, but recent studies show confounding effects of genetic background. Importantly, however, the enhancement of GSIS is robustly recapitulated with acute UCP2 knockdown in INS-1E insulinoma cells. UCP2 protein level in these cells is dynamically regulated, over at least a fourfold concentration range, by rapid proteolysis (half-life less than 1 h) opposing regulated gene transcription and mRNA translation. Degradation is catalysed by the cytosolic proteasome in an unprecedented pathway that is currently known to act only on UCP2 and UCP3. Evidence for proteasomal turnover of UCP2 includes sensitivity of degradation to classic proteasome inhibitors in cells, and reconstitution of degradation in vitro in mitochondria incubated with ubiquitin and the cytosolic 26S proteasome. These dynamic changes in UCP2 content may provide a fine level of control over GSIS in β-cells.</description><identifier>ISSN: 1462-8902</identifier><identifier>EISSN: 1463-1326</identifier><identifier>DOI: 10.1111/j.1463-1326.2010.01264.x</identifier><identifier>PMID: 21029310</identifier><language>eng</language><publisher>Oxford, UK: Oxford, UK : Blackwell Publishing Ltd</publisher><subject>Animals ; Bioenergetics ; Degradation ; Energy Metabolism - genetics ; Energy Metabolism - physiology ; Glucose ; Glucose - pharmacology ; Glucose tolerance ; glucose-stimulated insulin secretion ; INS-1E cells ; Insulin - metabolism ; Insulin Secretion ; Insulin-Secreting Cells - metabolism ; Insulinoma ; Ion Channels - genetics ; Ion Channels - physiology ; Mice ; Mice, Transgenic ; mitochondria ; Mitochondrial Proteins - genetics ; Mitochondrial Proteins - physiology ; Mitochondrial uncoupling protein 2 ; Oxidative phosphorylation ; Pancreas ; Phosphorylation ; proteasome ; Proteasome 26S ; proteasome endopeptidase complex ; Proteasome inhibitors ; Proteasomes ; protein degradation ; Proteins ; Proteolysis ; Reactive Oxygen Species - metabolism ; Secretion ; turnover ; Ubiquitin ; UCP2 ; UCP3 ; Uncoupling Protein 2</subject><ispartof>Diabetes, obesity & metabolism, 2010-10, Vol.12 (s2), p.134-140</ispartof><rights>2010 Blackwell Publishing Ltd</rights><rights>2010 Blackwell Publishing Ltd.</rights><rights>Copyright Wiley Subscription Services, Inc. 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This arrangement allows glucose-stimulated insulin secretion (GSIS) to be regulated by the coupling efficiency of oxidative phosphorylation. Uncoupling protein 2 (UCP2) modulates coupling efficiency and may regulate GSIS. Initial measurements of GSIS and glucose tolerance in Ucp2⁻/⁻ mice supported this model, but recent studies show confounding effects of genetic background. Importantly, however, the enhancement of GSIS is robustly recapitulated with acute UCP2 knockdown in INS-1E insulinoma cells. UCP2 protein level in these cells is dynamically regulated, over at least a fourfold concentration range, by rapid proteolysis (half-life less than 1 h) opposing regulated gene transcription and mRNA translation. Degradation is catalysed by the cytosolic proteasome in an unprecedented pathway that is currently known to act only on UCP2 and UCP3. Evidence for proteasomal turnover of UCP2 includes sensitivity of degradation to classic proteasome inhibitors in cells, and reconstitution of degradation in vitro in mitochondria incubated with ubiquitin and the cytosolic 26S proteasome. These dynamic changes in UCP2 content may provide a fine level of control over GSIS in β-cells.</description><subject>Animals</subject><subject>Bioenergetics</subject><subject>Degradation</subject><subject>Energy Metabolism - genetics</subject><subject>Energy Metabolism - physiology</subject><subject>Glucose</subject><subject>Glucose - pharmacology</subject><subject>Glucose tolerance</subject><subject>glucose-stimulated insulin secretion</subject><subject>INS-1E cells</subject><subject>Insulin - metabolism</subject><subject>Insulin Secretion</subject><subject>Insulin-Secreting Cells - metabolism</subject><subject>Insulinoma</subject><subject>Ion Channels - genetics</subject><subject>Ion Channels - physiology</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>mitochondria</subject><subject>Mitochondrial Proteins - genetics</subject><subject>Mitochondrial Proteins - physiology</subject><subject>Mitochondrial uncoupling protein 2</subject><subject>Oxidative phosphorylation</subject><subject>Pancreas</subject><subject>Phosphorylation</subject><subject>proteasome</subject><subject>Proteasome 26S</subject><subject>proteasome endopeptidase complex</subject><subject>Proteasome inhibitors</subject><subject>Proteasomes</subject><subject>protein degradation</subject><subject>Proteins</subject><subject>Proteolysis</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Secretion</subject><subject>turnover</subject><subject>Ubiquitin</subject><subject>UCP2</subject><subject>UCP3</subject><subject>Uncoupling Protein 2</subject><issn>1462-8902</issn><issn>1463-1326</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkM1u1DAQxy0Eoh_wChCJA6cs_ortHDigLbSVuhSprTiOHGdSvGSTrZ2I7Wv1QXgmnKbsgRNzGI_s339m_CckY3TBUnxYL5hUImeCqwWn6ZYyruRi94wc7h-eP9Y8NyXlB-QoxjWlVAqjX5IDzigvBaOHpFz5oXc_-q4O3rbZ2Ll-3La-u822oR_QdxnPUtrazgW0g3fZ74fcYdvGV-RFY9uIr5_OY3L95fP18iy_uDw9X366yJ0sjMyLFChVpWsslESBrElZ1ZRJ5oRQpa2pKZqqVBqpqLApjKuQ85opTbUWx-T93DbtczdiHGDj47SA7bAfI2jFpWHCyES--4dc92Po0m4gaFFKpoUyiTIz5UIfY8AGtsFvbLgHRmEyF9YweQiThzCZC4_mwi5J3zwNGKsN1nvhXzcT8HEGfvkW7_-7MZxcrqYq6fNZ7-OAu73ehp-gtNAFfP96Ct-WeiXl6gSKxL-d-cb2YG-Dj3BzlToLykz6rxHiD8BGnmo</recordid><startdate>201010</startdate><enddate>201010</enddate><creator>Brand, M.D</creator><creator>Parker, N</creator><creator>Affourtit, C</creator><creator>Mookerjee, S.A</creator><creator>Azzu, V</creator><general>Oxford, UK : Blackwell Publishing Ltd</general><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>FBQ</scope><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TK</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201010</creationdate><title>Mitochondrial uncoupling protein 2 in pancreatic β-cells</title><author>Brand, M.D ; Parker, N ; Affourtit, C ; Mookerjee, S.A ; Azzu, V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4584-5555e46b7de564e3e1f4e36d0141c3369ad085fb967e03bef58cbe22d1670773</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Bioenergetics</topic><topic>Degradation</topic><topic>Energy Metabolism - genetics</topic><topic>Energy Metabolism - physiology</topic><topic>Glucose</topic><topic>Glucose - pharmacology</topic><topic>Glucose tolerance</topic><topic>glucose-stimulated insulin secretion</topic><topic>INS-1E cells</topic><topic>Insulin - metabolism</topic><topic>Insulin Secretion</topic><topic>Insulin-Secreting Cells - metabolism</topic><topic>Insulinoma</topic><topic>Ion Channels - genetics</topic><topic>Ion Channels - physiology</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>mitochondria</topic><topic>Mitochondrial Proteins - genetics</topic><topic>Mitochondrial Proteins - physiology</topic><topic>Mitochondrial uncoupling protein 2</topic><topic>Oxidative phosphorylation</topic><topic>Pancreas</topic><topic>Phosphorylation</topic><topic>proteasome</topic><topic>Proteasome 26S</topic><topic>proteasome endopeptidase complex</topic><topic>Proteasome inhibitors</topic><topic>Proteasomes</topic><topic>protein degradation</topic><topic>Proteins</topic><topic>Proteolysis</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Secretion</topic><topic>turnover</topic><topic>Ubiquitin</topic><topic>UCP2</topic><topic>UCP3</topic><topic>Uncoupling Protein 2</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Brand, M.D</creatorcontrib><creatorcontrib>Parker, N</creatorcontrib><creatorcontrib>Affourtit, C</creatorcontrib><creatorcontrib>Mookerjee, S.A</creatorcontrib><creatorcontrib>Azzu, V</creatorcontrib><collection>AGRIS</collection><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Diabetes, obesity & metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brand, M.D</au><au>Parker, N</au><au>Affourtit, C</au><au>Mookerjee, S.A</au><au>Azzu, V</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mitochondrial uncoupling protein 2 in pancreatic β-cells</atitle><jtitle>Diabetes, obesity & metabolism</jtitle><addtitle>Diabetes Obes Metab</addtitle><date>2010-10</date><risdate>2010</risdate><volume>12</volume><issue>s2</issue><spage>134</spage><epage>140</epage><pages>134-140</pages><issn>1462-8902</issn><eissn>1463-1326</eissn><abstract>Pancreatic β-cells have remarkable bioenergetics in which increased glucose supply upregulates the cytosolic ATP/ADP ratio and increases insulin secretion. This arrangement allows glucose-stimulated insulin secretion (GSIS) to be regulated by the coupling efficiency of oxidative phosphorylation. Uncoupling protein 2 (UCP2) modulates coupling efficiency and may regulate GSIS. Initial measurements of GSIS and glucose tolerance in Ucp2⁻/⁻ mice supported this model, but recent studies show confounding effects of genetic background. Importantly, however, the enhancement of GSIS is robustly recapitulated with acute UCP2 knockdown in INS-1E insulinoma cells. UCP2 protein level in these cells is dynamically regulated, over at least a fourfold concentration range, by rapid proteolysis (half-life less than 1 h) opposing regulated gene transcription and mRNA translation. Degradation is catalysed by the cytosolic proteasome in an unprecedented pathway that is currently known to act only on UCP2 and UCP3. Evidence for proteasomal turnover of UCP2 includes sensitivity of degradation to classic proteasome inhibitors in cells, and reconstitution of degradation in vitro in mitochondria incubated with ubiquitin and the cytosolic 26S proteasome. These dynamic changes in UCP2 content may provide a fine level of control over GSIS in β-cells.</abstract><cop>Oxford, UK</cop><pub>Oxford, UK : Blackwell Publishing Ltd</pub><pmid>21029310</pmid><doi>10.1111/j.1463-1326.2010.01264.x</doi><tpages>7</tpages></addata></record> |
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| subjects | Animals Bioenergetics Degradation Energy Metabolism - genetics Energy Metabolism - physiology Glucose Glucose - pharmacology Glucose tolerance glucose-stimulated insulin secretion INS-1E cells Insulin - metabolism Insulin Secretion Insulin-Secreting Cells - metabolism Insulinoma Ion Channels - genetics Ion Channels - physiology Mice Mice, Transgenic mitochondria Mitochondrial Proteins - genetics Mitochondrial Proteins - physiology Mitochondrial uncoupling protein 2 Oxidative phosphorylation Pancreas Phosphorylation proteasome Proteasome 26S proteasome endopeptidase complex Proteasome inhibitors Proteasomes protein degradation Proteins Proteolysis Reactive Oxygen Species - metabolism Secretion turnover Ubiquitin UCP2 UCP3 Uncoupling Protein 2 |
| title | Mitochondrial uncoupling protein 2 in pancreatic β-cells |
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