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 prooxidant effects. We examined the bioenergetic effects of two mitochondrial-targeted CoQ analogs in their quinol forms, MitoQ (mitoquinol) and SkQ1 (plastoquinonyl-decyl-triphenylphosphonium), in bovine aortic endothelial (BAE) 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 (OCRATP) (IC50 189 ± 13 nM for MitoQ and 181 ± 7 for SKQ1, difference non-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 using mitochondrial-targeted dihydroethidium and both increased H2O2 production from mitochondria of cells treated prior to isolation of the organelles. The MnSOD mimetic, manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin, did not alter or actually enhanced the actions of the targeted CoQ analogs to reduce OCRATP. In contrast, N-acetylcysteine mitigated this effect of MitoQ and SkQ1. In summary, our data demonstrate important bioenergetic effects of targeted CoQ analogs. Moreover, these effects are mediated, at least in part, through superoxide production but dependent on conversion to H2O2. These bioenergetic and redox actions need to be considered as these compounds are developed for therapeutic purposes.
- Received April 14, 2012.
- Revision received May 31, 2012.
- Accepted May 31, 2012.
- The American Society for Pharmacology and Experimental Therapeutics