Uncoupling protein-2 expression and effects on mitochondrial membrane potential and oxidant stress in heart tissue

Jesús A. Cabrera, Elizabeth A. Ziemba, Robert Colbert, Rosemary F. Kelly, Michael Kuskowski, Edgar A. Arriaga, Wim Sluiter, Dirk J. Duncker, Herbert B. Ward, Edward O. McFalls

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Myocardial uncoupling protein (UCP)-2 is increased with chronic peroxisome proliferator-activated receptor γ (PPARγ) stimulation, but the effect on membrane potential and superoxide is unclear. Wild-type (WT) and UCP-2 knockout (KO) mice were given a 3-week diet of control (C) or the PPARγ agonist pioglitazone (PIO; 50 μg/g-chow per day). In isolated mitochondria, UCP-2 content by Western blots, membrane potential (ΔΨm) by tetraphenylphosphonium (TPP), and relative superoxide levels by dihydroethidium (DHE) were measured. Oxygen respiration was determined at baseline and after 10 min anoxia-reoxygenation. PIO induced a 2-fold increase in UCP-2 and nuclear-bound PGC1α in WT mice with no UCP-2 expression in KO mice. Mitochondrial ΔΨm from WT mice on C and PIO diets was -166 ± 4 mV and -147 ± 6 mV, respectively (P < 0.05). These values were lower than in UCP-2 KO mice on C and PIO (-180 ± 4 mV and -180 ± 4 mV, respectively; P < 0.05). Maximal complex III inhibitable superoxide from WT mice on C and PIO diets was 22.5 ± 1.3 and 17.8 ± 1.1 AU, respectively (P < 0.05), and were lower than UCP-2 KO on C and PIO (32.9 ± 2.3 and 29.2 ± 1.9 AU, respectively; P < 0.05). Postanoxia, the respiratory control index (RCI) in mitochondria from WT mice with and without PIO was 2.5 ± 0.3 and 2.4 ± 0.2, respectively, and exceeded that of UCP-2 KO mice on C and PIO (1.2 ± 0.1 and 1.4 ± 0.1, respectively; P < 0.05). In summary, chronic PPARγ stimulation leads to depolarization of the inner membrane and reduced superoxide of isolated heart mitochondria, which was critically dependent on increased expression of UCP-2. Thus, UCP-2 expression affords resistance to brief anoxia-reoxygenation.

Original languageEnglish (US)
Pages (from-to)383-390
Number of pages8
JournalTranslational Research
Issue number5
StatePublished - May 2012

Bibliographical note

Funding Information:
Supported by Grant NHLBI089307 from the National Institutes of Health (to E.M.), VA Merit Review (to R.K.), and American Heart Association (Midwest Affiliate) Undergraduate Student Research Fellowship Award (to R.C.).


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