PMID- 22661629
OWN - NLM
STAT- MEDLINE
DCOM- 20130307
LR  - 20211021
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 342
IP  - 3
DP  - 2012 Sep
TI  - Bioenergetic effects of mitochondrial-targeted coenzyme Q analogs in endothelial 
      cells.
PG  - 709-19
LID - 10.1124/jpet.112.195586 [doi]
AB  - Mitochondrial-targeted analogs of coenzyme Q (CoQ) are under development to 
      reduce oxidative damage induced by a variety of disease states. However, there is 
      a need to understand the bioenergetic effects of these agents and whether or not 
      these effects are related to redox properties, including their known pro-oxidant 
      effects. We examined the bioenergetic effects of two mitochondrial-targeted CoQ 
      analogs in their quinol forms, mitoquinol (MitoQ) and 
      plastoquinonyl-decyl-triphenylphosphonium (SkQ1), in bovine aortic endothelial 
      cells. We used an extracellular oxygen and proton flux analyzer to assess 
      mitochondrial action at the intact-cell level. Both agents, in dose-dependent 
      fashion, reduced the oxygen consumption rate (OCR) directed at ATP turnover 
      (OCR(ATP)) (IC(5)(0) values of 189 +/- 13 nM for MitoQ and 181 +/- 7 for SKQ1; difference 
      not significant) while not affecting or mildly increasing basal oxygen 
      consumption. Both compounds increased extracellular acidification in the basal 
      state consistent with enhanced glycolysis. Both compounds enhanced mitochondrial 
      superoxide production assessed by using mitochondrial-targeted dihydroethidium, 
      and both increased H(2)O(2) production from mitochondria of cells treated before 
      isolation of the organelles. The manganese superoxide dismutase mimetic 
      manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin did not alter or actually 
      enhanced the actions of the targeted CoQ analogs to reduce OCR(ATP). In contrast, 
      N-acetylcysteine mitigated this effect of MitoQ and SkQ1. In summary, our data 
      demonstrate the important bioenergetic effects of targeted CoQ analogs. Moreover, 
      these effects are mediated, at least in part, through superoxide production but 
      depend on conversion to H(2)O(2). These bioenergetic and redox actions need to be 
      considered as these compounds are developed for therapeutic purposes.
FAU - Fink, Brian D
AU  - Fink BD
AD  - Departments of Internal Medicine/Endocrinology, University of Iowa, Iowa City, 
      Iowa, USA.
FAU - Herlein, Judith A
AU  - Herlein JA
FAU - Yorek, Mark A
AU  - Yorek MA
FAU - Fenner, Amanda M
AU  - Fenner AM
FAU - Kerns, Robert J
AU  - Kerns RJ
FAU - Sivitz, William I
AU  - Sivitz WI
LA  - eng
GR  - R01 HL073166/HL/NHLBI NIH HHS/United States
GR  - T32 GM067795/GM/NIGMS NIH HHS/United States
GR  - 5R01HL073166/HL/NHLBI NIH HHS/United States
GR  - T32GM067795/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120601
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (10-(6'-plastoquinonyl)decyltriphenylphosphonium)
RN  - 0 (Metalloporphyrins)
RN  - 0 (Onium Compounds)
RN  - 0 (Organophosphorus Compounds)
RN  - 0 (Protons)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Trityl Compounds)
RN  - 11062-77-4 (Superoxides)
RN  - 1339-63-5 (Ubiquinone)
RN  - 15912-74-0 (triphenylmethylphosphonium)
RN  - 65M41NIO61 (mitoquinol)
RN  - 70649-54-6 (tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - OAC30J69CN (Plastoquinone)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - Acetylcysteine/pharmacology
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Aorta/drug effects/metabolism/physiology
MH  - Cattle
MH  - Cell Respiration/drug effects/physiology
MH  - Cells, Cultured
MH  - Endothelial Cells/drug effects/metabolism/*physiology
MH  - Energy Metabolism/drug effects
MH  - Glycolysis/drug effects/physiology
MH  - Hydrogen Peroxide/metabolism
MH  - Metalloporphyrins/pharmacology
MH  - Mitochondria/drug effects/*metabolism/*physiology
MH  - Onium Compounds/pharmacology
MH  - Organophosphorus Compounds/pharmacology
MH  - Oxidation-Reduction
MH  - Oxidative Stress/drug effects/physiology
MH  - Oxygen Consumption/drug effects/physiology
MH  - Plastoquinone/analogs & derivatives/pharmacology
MH  - Protons
MH  - Reactive Oxygen Species/metabolism
MH  - Superoxide Dismutase/metabolism
MH  - Superoxides/metabolism
MH  - Trityl Compounds/pharmacology
MH  - Ubiquinone/*analogs & derivatives/*metabolism/pharmacology
PMC - PMC3422527
EDAT- 2012/06/05 06:00
MHDA- 2013/03/08 06:00
PMCR- 2013/09/01
CRDT- 2012/06/05 06:00
PHST- 2012/06/05 06:00 [entrez]
PHST- 2012/06/05 06:00 [pubmed]
PHST- 2013/03/08 06:00 [medline]
PHST- 2013/09/01 00:00 [pmc-release]
AID - jpet.112.195586 [pii]
AID - 3787057 [pii]
AID - 10.1124/jpet.112.195586 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2012 Sep;342(3):709-19. doi: 10.1124/jpet.112.195586. Epub 
      2012 Jun 1.