Publication Date:
2013-08-02
Description:
Background: Thiazolidinedione are antidiabetic agents that increase insulin sensitivity but reduce glucoseoxidation, state 3 respiration, and activity of complex I of the mitochondrial respiratory chain(MRC). Mechanisms of the latter effects are unclear. The aim of this study was to determinethe mechanisms by which pioglitazone (PGZ), a member of the thiazolidinedione class ofantidiabetic agents, decreases the activity of MRC. In isolated mitochondria from mouseliver, we measured the effects of PGZ treatment on MRC complexes activity, fully-assembledcomplex I and its subunits, gene expression of complex I and III subunits, and [3H]pioglitazone binding to mitochondrial complexes. Results: (1) In vitro, PGZ decreased activity of complexes I and III of the MRC, but in vivo onlycomplex I activity was decreased in mice treated for 12 weeks with 10 mg/Kg/day of PGZ.(2) In vitro treatment of isolated liver mitochondria with PGZ disassembled complex Iresulting in the formation of several subcomplexes. In mice treated with PGZ, fullyassembled complex I was increased and two additional subcomplexes were found. Formationof supercomplexes CI+CIII2+CIVn and CI+CIII2 decreased in mouse liver mitochondriaexposed to PGZ, while formation of these supercomplexes was increased in mice treated withPGZ. Two dimensional analysis of complex I using BN/SDS-PAGE showed that in vitroPGZ induced the formation of four subcomplexes of 600 (B), 400 (C), 350 (D), and 250 (E)kDa, respectively. Subcomplexes B and C had NADH:dehydrogenase activity, whilesubcomplexes C and D contained subunits of complex I membrane arm. (3) Autoradiographyand coimmunoprecipitation assays showed [3H]PGZ binding to subunits NDUFA9,NDUFB6, and NDUFA6. (4) Treatment with PGZ increased mitochondrial gene transcriptionin mice liver and HepG2 cells. (5) In these cells, PGZ decreased intracellular ATP contentand enhanced gene expression of specific protein-1 and peroxisome-proliferator activatedreceptor (PPAR)-gamma coactivator-1alpha (PGC-1alpha). Conclusions: PGZ binds complex I subunits, which induces disassembly of this complex, reduces itsactivity, depletes cellular ATP, and, in mice and HepG2 cells, upregulates nuclear DNAencodedgene expression of complex I and III subunits.
Electronic ISSN:
1741-7007
Topics:
Biology
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