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Selective Targeting of a Redox-active Ubiquinone to Mitochondria within Cells
Open accessAbstract
With the recognition of the central role of mitochondria in apoptosis, there is a need to develop specific tools to manipulate mitochondrial function within cells. Here we report on the development of a novel antioxidant that selectively blocks mitochondrial oxidative damage, enabling the roles of mitochondrial oxidative stress in different types of cell death to be inferred. This antioxidant, named mitoQ, is a ubiquinone derivative targeted to mitochondria by covalent attachment to a lipophilic triphenylphosphonium cation through an aliphatic carbon chain. Due to the large mitochondrial membrane potential, the cation was accumulated within mitochondria inside cells, where the ubiquinone moiety inserted into the lipid bilayer and was reduced by the respiratory chain. The ubiquinol derivative thus formed was an effective antioxidant that prevented lipid peroxidation and protected mitochondria from oxidative damage. After detoxifying a reactive oxygen species, the ubiquinol moiety was regenerated by the respiratory chain enabling its antioxidant activity to be recycled. In cell culture studies, the mitochondrially localized antioxidant protected mammalian cells from hydrogen peroxide-induced apoptosis but not from apoptosis induced by staurosporine or tumor necrosis factor-alpha. This was compared with untargeted ubiquinone analogs, which were ineffective in preventing apoptosis. These results suggest that mitochondrial oxidative stress may be a critical step in apoptosis induced by hydrogen peroxide but not for apoptosis induced by staurosporine or tumor necrosis factor-alpha. We have shown that selectively manipulating mitochondrial antioxidant status with targeted and recyclable antioxidants is a feasible approach to investigate the role of mitochondrial oxidative damage in apoptotic cell death. This approach will have further applications in investigating mitochondrial dysfunction in a range of experimental models.
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In the citing paper
“There is extensive in vitro evidence that the concentrations of MitoQ used here have no impact on mitochondrial functions, such as ATP production, membrane potential, or ROS production in cells or mitochondria, but do prevent mitochondrial oxidative damage under conditions that lead to oxidative stress (Kelso et al., 2001; Jauslin et al., 2003; Saretzki et al., 2003; Asin-Cayuelaa et al., 2004).”
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 Kelso et al., 2001
In the citing paper
“This small molecule consists of the antioxidant ubiquinol linked to the lipophilic cation triphenylphosphonium (500).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [500]
In the citing paper
“Moreover, treatment with MitoQ, a substance known to scavenge matrix mtROS (see Section 6) [314,315], gave contrasting results: only IL-1β cleavage was reduced, whereas TNF and IL-10 levels remained unaltered.”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [315]
In the citing paper
“whereas MitoQ is an analog of ubiquinone and prevents lipid peroxidation in mitochondrial membranes [314,315].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [315]
In the citing paper
“One approach to this involves the synthesis of compounds linking agents such as redox forms of quinone (ubiquinol and ubiquinone) or vitamin E to form alkylated triphenylphosphonium compounds. These are lipophilic cations avidly taken up into the relatively negative mitochondrial matrix (162).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [162]
In the citing paper
“Two such compounds (alkyltriphenylphosphonium cations) incorporating ubiquinone or vitamin E, termed mitoQ and mitoVit E, respectively, have been synthesized (162).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [162]
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Metadata
- Authors
- Kelso, G. F., Porteous, C. M., Coulter, C. V., Hughes, G., Porteous, W. K., Ledgerwood, E. C., Smith, R. A. J., & Murphy, M. P.
- Affiliations
- University of Otago (NZ)
- Corresponding author
- Murphy, Michael P.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-02
- Volume
- 276
- Issue
- 7
- Pages
- 4588-4596
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2017692041
- Cited by
- 1,091
- References
- 51
- Citations by year
- 2026: 33 · 2025: 33 · 2024: 53 · 2023: 52 · 2022: 57 · 2021: 65 · 2020: 60 · 2019: 43 · 2018: 57 · 2017: 50 · 2016: 52 · 2015: 51 · 2014: 43 · 2013: 37 · 2012: 47
- FWCI
- 7.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- MitoQ, mitochondrial targeting, triphenylphosphonium cation, mitochondrial membrane potential, mitochondrial oxidative stress, hydrogen peroxide-induced apoptosis, staurosporine-induced apoptosis, lipid peroxidation, electron transport chain, mitochondrial dysfunction
- MeSH terms
- Animals, Antioxidants, Biological Transport, Active, Cattle, Cell Survival, Electron Transport, Humans, Hydrogen Peroxide, Mitochondria, Multienzyme Complexes, Organophosphorus Compounds, Oxidation-Reduction, Tumor Cells, Cultured, Ubiquinone, Apoptosis, Oxidative Stress, Jurkat Cells, Rats
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