Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)--relationship to newly identified mitochondrial pyruvate carrier proteins.
Thiazolidinedione (TZD) insulin sensitizers have the potential to effectively treat a number of human diseases, however the currently available agents have dose-limiting side effects that are mediated via activation of the transcription factor PPARγ. We have recently shown PPARγ-independent actions...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3655167?pdf=render |
| _version_ | 1818113724159885312 |
|---|---|
| author | Jerry R Colca William G McDonald Gregory S Cavey Serena L Cole Danielle D Holewa Angela S Brightwell-Conrad Cindy L Wolfe Jean S Wheeler Kristin R Coulter Peter M Kilkuskie Elena Gracheva Yulia Korshunova Michelle Trusgnich Robert Karr Sandra E Wiley Ajit S Divakaruni Anne N Murphy Patrick A Vigueira Brian N Finck Rolf F Kletzien |
| author_facet | Jerry R Colca William G McDonald Gregory S Cavey Serena L Cole Danielle D Holewa Angela S Brightwell-Conrad Cindy L Wolfe Jean S Wheeler Kristin R Coulter Peter M Kilkuskie Elena Gracheva Yulia Korshunova Michelle Trusgnich Robert Karr Sandra E Wiley Ajit S Divakaruni Anne N Murphy Patrick A Vigueira Brian N Finck Rolf F Kletzien |
| author_sort | Jerry R Colca |
| collection | DOAJ |
| description | Thiazolidinedione (TZD) insulin sensitizers have the potential to effectively treat a number of human diseases, however the currently available agents have dose-limiting side effects that are mediated via activation of the transcription factor PPARγ. We have recently shown PPARγ-independent actions of TZD insulin sensitizers, but the molecular target of these molecules remained to be identified. Here we use a photo-catalyzable drug analog probe and mass spectrometry-based proteomics to identify a previously uncharacterized mitochondrial complex that specifically recognizes TZDs. These studies identify two well-conserved proteins previously known as brain protein 44 (BRP44) and BRP44 Like (BRP44L), which recently have been renamed Mpc2 and Mpc1 to signify their function as a mitochondrial pyruvate carrier complex. Knockdown of Mpc1 or Mpc2 in Drosophila melanogaster or pre-incubation with UK5099, an inhibitor of pyruvate transport, blocks the crosslinking of mitochondrial membranes by the TZD probe. Knockdown of these proteins in Drosophila also led to increased hemolymph glucose and blocked drug action. In isolated brown adipose tissue (BAT) cells, MSDC-0602, a PPARγ-sparing TZD, altered the incorporation of (13)C-labeled carbon from glucose into acetyl CoA. These results identify Mpc1 and Mpc2 as components of the mitochondrial target of TZDs (mTOT) and suggest that understanding the modulation of this complex, which appears to regulate pyruvate entry into the mitochondria, may provide a viable target for insulin sensitizing pharmacology. |
| first_indexed | 2024-12-11T03:39:23Z |
| format | Article |
| id | doaj.art-810bfe5fc88043a1a3d87fdcdaabf016 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T03:39:23Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-810bfe5fc88043a1a3d87fdcdaabf0162022-12-22T01:22:10ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0185e6155110.1371/journal.pone.0061551Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)--relationship to newly identified mitochondrial pyruvate carrier proteins.Jerry R ColcaWilliam G McDonaldGregory S CaveySerena L ColeDanielle D HolewaAngela S Brightwell-ConradCindy L WolfeJean S WheelerKristin R CoulterPeter M KilkuskieElena GrachevaYulia KorshunovaMichelle TrusgnichRobert KarrSandra E WileyAjit S DivakaruniAnne N MurphyPatrick A VigueiraBrian N FinckRolf F KletzienThiazolidinedione (TZD) insulin sensitizers have the potential to effectively treat a number of human diseases, however the currently available agents have dose-limiting side effects that are mediated via activation of the transcription factor PPARγ. We have recently shown PPARγ-independent actions of TZD insulin sensitizers, but the molecular target of these molecules remained to be identified. Here we use a photo-catalyzable drug analog probe and mass spectrometry-based proteomics to identify a previously uncharacterized mitochondrial complex that specifically recognizes TZDs. These studies identify two well-conserved proteins previously known as brain protein 44 (BRP44) and BRP44 Like (BRP44L), which recently have been renamed Mpc2 and Mpc1 to signify their function as a mitochondrial pyruvate carrier complex. Knockdown of Mpc1 or Mpc2 in Drosophila melanogaster or pre-incubation with UK5099, an inhibitor of pyruvate transport, blocks the crosslinking of mitochondrial membranes by the TZD probe. Knockdown of these proteins in Drosophila also led to increased hemolymph glucose and blocked drug action. In isolated brown adipose tissue (BAT) cells, MSDC-0602, a PPARγ-sparing TZD, altered the incorporation of (13)C-labeled carbon from glucose into acetyl CoA. These results identify Mpc1 and Mpc2 as components of the mitochondrial target of TZDs (mTOT) and suggest that understanding the modulation of this complex, which appears to regulate pyruvate entry into the mitochondria, may provide a viable target for insulin sensitizing pharmacology.http://europepmc.org/articles/PMC3655167?pdf=render |
| spellingShingle | Jerry R Colca William G McDonald Gregory S Cavey Serena L Cole Danielle D Holewa Angela S Brightwell-Conrad Cindy L Wolfe Jean S Wheeler Kristin R Coulter Peter M Kilkuskie Elena Gracheva Yulia Korshunova Michelle Trusgnich Robert Karr Sandra E Wiley Ajit S Divakaruni Anne N Murphy Patrick A Vigueira Brian N Finck Rolf F Kletzien Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)--relationship to newly identified mitochondrial pyruvate carrier proteins. PLoS ONE |
| title | Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)--relationship to newly identified mitochondrial pyruvate carrier proteins. |
| title_full | Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)--relationship to newly identified mitochondrial pyruvate carrier proteins. |
| title_fullStr | Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)--relationship to newly identified mitochondrial pyruvate carrier proteins. |
| title_full_unstemmed | Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)--relationship to newly identified mitochondrial pyruvate carrier proteins. |
| title_short | Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)--relationship to newly identified mitochondrial pyruvate carrier proteins. |
| title_sort | identification of a mitochondrial target of thiazolidinedione insulin sensitizers mtot relationship to newly identified mitochondrial pyruvate carrier proteins |
| url | http://europepmc.org/articles/PMC3655167?pdf=render |
| work_keys_str_mv | AT jerryrcolca identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT williamgmcdonald identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT gregoryscavey identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT serenalcole identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT danielledholewa identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT angelasbrightwellconrad identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT cindylwolfe identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT jeanswheeler identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT kristinrcoulter identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT petermkilkuskie identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT elenagracheva identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT yuliakorshunova identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT michelletrusgnich identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT robertkarr identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT sandraewiley identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT ajitsdivakaruni identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT annenmurphy identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT patrickavigueira identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT briannfinck identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins AT rolffkletzien identificationofamitochondrialtargetofthiazolidinedioneinsulinsensitizersmtotrelationshiptonewlyidentifiedmitochondrialpyruvatecarrierproteins |