Interactions of Mitochondria-targeted and Untargeted Ubiquinones with the Mitochondrial Respiratory Chain and Reactive Oxygen Species
Open accessAbstract
Antioxidants, such as ubiquinones, are 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 they can also be pro-oxidants or electron carriers that facilitate respiration. Recently we developed a mitochondria-targeted ubiquinone (MitoQ10) that accumulates within mitochondria. MitoQ10 has been used to prevent mitochondrial oxidative damage and to infer the involvement of mitochondrial reactive oxygen species in signaling pathways. However, uncertainties remain about the mitochondrial reduction of MitoQ10, its oxidation by the respiratory chain, and its pro-oxidant potential. Therefore, we compared MitoQ analogs of varying alkyl chain lengths (MitoQn, n = 3-15) with untargeted exogenous ubiquinones. We found that MitoQ10 could not restore respiration in ubiquinone-deficient mitochondria because oxidation of MitoQ analogs by complex III was minimal. Complex II and glycerol 3-phosphate dehydrogenase reduced MitoQ analogs, and the rate depended on chain length. Because of its rapid reduction and negligible oxidation, MitoQ10 is a more effective antioxidant against lipid peroxidation, peroxynitrite and superoxide. Paradoxically, exogenous ubiquinols also autoxidize to generate superoxide, but this requires their deprotonation in the aqueous phase. Consequently, in the presence of phospholipid bilayers, the rate of autoxidation is proportional to ubiquinol hydrophilicity. Superoxide production by MitoQ10 was insufficient to damage aconitase but did lead to hydrogen peroxide production and nitric oxide consumption, both of which may affect cell signaling pathways. Our results comprehensively describe the interaction of exogenous ubiquinones with mitochondria and have implications for their rational design and use as therapies and as research tools to probe mitochondrial function.
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MitoQ possesses the qualities of crossing the blood-brain barrier and selectively concentrating in mitochondria.
“The recently developed, mitochondria-targeted antioxidant MitoQ (mitoquinone mesylate: [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cycloheexadienlyl) decyl triphenylphosphonium methanesulfonate]) possesses these qualities (James et al., 2005, 2007; Murphy and Smith, 2007).”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as James et al., 2005
The passage labeled Abstract states that MitoQ10 selectively accumulates within mitochondria in isolated preparations, cells, and in vivo. It does not establish that MitoQ crosses the blood-brain barrier; a search for blood-brain barrier and brain penetration found no supporting passage in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMitoQ cannot substitute for endogenous ubiquinone in the electron transport chain but primarily acts as an antioxidant capable of continuous regeneration by complex II.
“Therefore, it cannot substitute for endogenous ubiquinone in the electron transport chain but primarily acts as an antioxidant capable of continuous regeneration by complex II (James et al., 2005, 2007; Rodriguez-Cuenca et al., 2010).”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as James et al., 2005
MitoQ may prevent damage downstream of O2·- by directly detoxifying lipid-derived radicals and reactive nitrogen species.
“MitoQ may also prevent damage downstream of O2·- by directly detoxifying lipid-derived radicals and reactive nitrogen species”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as James et al., 2005
MitoQ may prevent damage downstream of O2·- indirectly through effective recycling of α-tocopherol.
“or indirectly through effective recycling of α-tocopherol”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as James et al., 2005
The Results passages describe MitoQ’s antioxidant activity and recycling of MitoQ to its active form, but do not address recycling of α-tocopherol. Searches for “tocopherol” and “vitamin E regeneration recycling” found no passage supporting the specific mechanism attributed to this paper. (LLM, conf=0.75)
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- Authors
- James, A. M., Cochemé, H. M., Smith, R. A. J., & Murphy, M. P.
- Affiliations
- MRC Mitochondrial Biology Unit (GB)
- University of Otago (NZ)
- Corresponding author
- Murphy, Michael P.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-06
- Volume
- 280
- Issue
- 22
- Pages
- 21295-21312
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2010524294
- Cited by
- 353
- References
- 98
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 14 · 2023: 13 · 2022: 20 · 2021: 16 · 2020: 20 · 2019: 15 · 2018: 11 · 2017: 13 · 2016: 12 · 2015: 14 · 2014: 20 · 2013: 19 · 2012: 25
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- mitochondrial respiratory chain, cytochrome bc1 complex, superoxide production, lipid peroxidation, peroxynitrite, hydrogen peroxide, nitric oxide consumption, aconitase, glycerol-3-phosphate dehydrogenase, alkyl chain length, mitochondrial antioxidants, mitochondrial oxidative damage
- MeSH terms
- Aconitate Hydratase, Animals, Antioxidants, Binding Sites, Cattle, Dose-Response Relationship, Drug, Electron Transport, Fatty Acids, Glycerolphosphate Dehydrogenase, Hydrogen Peroxide, Mitochondria, Mitochondria, Liver, Models, Biological, Models, Chemical, Models, Molecular, Myocardium, Nitric Oxide, Magnetic Resonance Spectroscopy, Oxidation-Reduction, Oxygen, Oxygen Consumption, Phosphorylation, Protein Binding, Saccharomyces cerevisiae, Sulfhydryl Compounds, Superoxides, Time Factors, Ubiquinone, Lipid Peroxidation, Signal Transduction, Reactive Oxygen Species, Oxidative Stress, Rats
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