MiP2005: Session 5

Mitochondrial Physiology Network 10.9: 65-66 (2005) - download pdf


Interactions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species: implications for the use of exogenous ubiquinones as therapies and experimental tools.

Andrew M James, HM Cochemé, RAJ Smith, MP Murphy

Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom. - aj@mrc-dunn.cam.ac.uk

    Mitochondrial reactive oxygen species (ROS) production plays a central role in oxidative damage and redox signalling. Consequently exogenous antioxidants, such as ubiquinones, have been widely used in mitochondrial studies as both potential therapies and useful research tools. However, the effects of exogenous ubiquinones can be difficult to interpret because in addition to being antioxidants they can also be pro-oxidants or facilitate respiration by acting as electron carriers. Recently we developed a mitochondria-targeted ubiquinone (MitoQ10) that accumulates within mitochondria due to the membrane potential, greatly increasing its effectiveness as an antioxidant. MitoQ10 has been used to prevent mitochondrial oxidative damage and to infer the involvement of mitochondrial ROS in signalling pathways. However, uncertainties remain about the mitochondrial reduction of MitoQ10 to its antioxidant ubiquinol form, the extent of its oxidation by the respiratory chain and its pro-oxidant potential.

    To address these issues, we have compared MitoQ analogs of varying alkyl chain lengths (MitoQn, n = 3, 5, 10, 15) with untargeted exogenous ubiquinones. We found that MitoQ10 could not restore respiration in ubiquinone-deficient mitochondria, while untargeted ubiquinones could. This occurred because oxidation of MitoQ analogs by complex III was minimal, probably due to their limited partition into the core of phospholipid bilayers. In contrast, MitoQ analogs were well reduced by complex II and glycerol-3-phosphate dehydrogenase, and this rate of reduction depended on chain length. Because of its rapid reduction and negligible oxidation, MitoQ10 persisted in situ in its active ubiquinol form, making it an effective antioxidant against lipid peroxidation, peroxynitrite and superoxide in the lipid phase. Paradoxically, exogenous ubiquinols also autoxidize to generate superoxide but we show this requires their deprotonation to the ubiquinolate anion in the aqueous phase. Consequently, in the presence of phospholipid bilayers, ubiquinol hydrophobicity determines the balance between antioxidant and pro-oxidant reactions. Superoxide production by MitoQ10 within intact mitochondria was insufficient to damage aconitase, but did lead to hydrogen peroxide production and nitric oxide consumption, both of which may affect cell signalling pathways. Finally MitoQ10 was not an effective antioxidant against peroxides, even though it can prevent H2O2-induced cell death. Our results provide a comprehensive description of how exogenous ubiquinones interact with mitochondria and ROS and help clarify the interpretation of experiments using these compounds. These findings have broad implications for the rational design and use of exogenous ubiquinones as therapies and as research tools to probe mitochondrial function.

1.  James AM, Smith RAJ, Murphy MP (2004) Arch. Biochem. Biophys. 423: 47-56.

2.  James AM, Cocheme HM, Smith RAJ, Murphy MP (2005) J. Biol. Chem., in press.

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