Fine-tuning the hydrophobicity of a mitochondria-targeted antioxidant
Abstract
The mitochondria‐targeted antioxidant MitoQ comprises a ubiquinol moiety covalently attached through an aliphatic carbon chain to the lipophilic triphenylphosphonium cation. This cation drives the membrane potential‐dependent accumulation of MitoQ into mitochondria, enabling the ubiquinol antioxidant to prevent mitochondrial oxidative damage far more effectively than untargeted antioxidants. We sought to fine‐tune the hydrophobicity of MitoQ so as to control the extent of its membrane binding and penetration into the phospholipid bilayer, and thereby regulate its partitioning between the membrane and aqueous phases within mitochondria and cells. To do this, MitoQ variants with 3, 5, 10 and 15 carbon aliphatic chains were synthesised. These molecules had a wide range of hydrophobicities with octan‐1‐ol/phosphate buffered saline partition coefficients from 2.8 to 20 000. All MitoQ variants were accumulated into mitochondria driven by the membrane potential, but their binding to phospholipid bilayers varied from negligible for MitoQ3 to essentially total for MitoQ15. Despite the span of hydrophobicites, all MitoQ variants were effective antioxidants. Therefore, it is possible to fine‐tune the degree of membrane association of MitoQ and other mitochondria targeted compounds, without losing antioxidant efficacy. This indicates how the uptake and distribution of mitochondria‐targeted compounds within mitochondria and cells can be controlled, thereby facilitating investigations of mitochondrial oxidative damage.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Retention and accumulation of TPP+ compounds is dependent on the alkyl chain length.
“Previous studies have shown that the effects of different carbon chain lengths which link the ubiquinol moiety to the TPP+ group showed that retention and accumulation of the compounds is dependent on the alkyl chain length [17,21,31].”
From Mitochondrially targeted compounds and their impact on cellular bioenergetics (2013) · cites this paper as [31]
Cites
Selective Targeting of a Redox-active Ubiquinone to Mitochondria within Cells
Kelso, G. F., Porteous, C. M., Coulter, C. V., Hughes, G., Porteous, W. K., Ledgerwood, E. C., Smith, R. A. J., & Murphy, M. P. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m009093200 · Cited by 1,091 · see citing works
Self-citationMitochondria, oxygen free radicals, disease and ageing
Raha, S., & Robinson, B. H. (2000) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)01674-1 · Cited by 1,066 · see citing works
Selective targeting of bioactive compounds to mitochondria
Murphy, M. P. (1997) · Trends in Biotechnology · doi:10.1016/s0167-7799(97)01068-8 · Cited by 366 · see citing works
Self-citationJauslin, M. L., Meier, T., Smith, R. A. J., & Murphy, P. M. (2003) · The FASEB Journal · doi:10.1096/fj.03-0240fje · Cited by 358 · see citing works
Self-citationSaretzki, G., Murphy, M. P., & Von Zglinicki, T. (2003) · Aging Cell · doi:10.1046/j.1474-9728.2003.00040.x · Cited by 203 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Targeting Antioxidants to Mitochondria by Conjugation to Lipophilic Cations
Murphy, M. P., & Smith, R. A. J. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.47.120505.105110 · Cited by 1,173 · see citing works
Self-citationTargeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury
Adlam, V. J., Harrison, J. C., Porteous, C. M., James, A. M., Smith, R. A. J., Murphy, M. P., & Sammut, I. A. (2005) · The FASEB Journal · doi:10.1096/fj.05-3718com · Cited by 618 · see citing works
Self-citationMcManus, M. J., Murphy, M. P., & Franklin, J. L. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0552-11.2011 · Cited by 432 · see citing works
Self-citationMitochondria-Targeted Small Molecule Therapeutics and Probes
Smith, R. A. J., Hartley, R. C., & Murphy, M. P. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.3969 · Cited by 399 · see citing works
Self-citationMitochondrially targeted compounds and their impact on cellular bioenergetics
Reily, C., Mitchell, T., Chacko, B. K., Benavides, G. A., Murphy, M. P., & Darley-Usmar, V. M. (2013) · Redox Biology · doi:10.1016/j.redox.2012.11.009 · Cited by 227 · see citing works
Self-citationMitochondrial uncouplers with an extraordinary dynamic range
Lou, P.-H., Hansen, B. S., Olsen, P. H., Tullin, S., Murphy, M. P., & Brand, M. D. (2007) · Biochemical Journal · doi:10.1042/bj20070606 · Cited by 141 · see citing works
Self-citationReactive Oxygen and Targeted Antioxidant Administration in Endothelial Cell Mitochondria
O'Malley, Y., Fink, B. D., Ross, N. C., Prisinzano, T. E., & Sivitz, W. I. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m608268200 · Cited by 123 · see citing works
Porteous, C. M., Logan, A., Evans, C., Ledgerwood, E. C., Menon, D. K., Aigbirhio, F., Smith, R. A. J., & Murphy, M. P. (2010) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2010.06.001 · Cited by 121 · see citing works
Self-citationMitochondrial Targeted Coenzyme Q, Superoxide, and Fuel Selectivity in Endothelial Cells
Fink, B. D., O'Malley, Y., Dake, B. L., Ross, N. C., Prisinzano, T. E., & Sivitz, W. I. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004250 · Cited by 21 · see citing works
- Authors
- Asin-Cayuela, J., Manas, A.-R. B., James, A. M., Smith, R. A. J., & Murphy, M. P.
- Affiliations
- University of Otago (NZ)
- MRC Mitochondrial Biology Unit (GB)
- Corresponding author
- Murphy, Michael P.
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 2004-07
- Volume
- 571
- Issue
- 1-3
- Pages
- 9-16
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- OpenAlex
- W2002625920
- Cited by
- 184
- References
- 5
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 3 · 2023: 10 · 2022: 5 · 2021: 12 · 2020: 10 · 2019: 9 · 2018: 9 · 2017: 17 · 2016: 7 · 2015: 4 · 2014: 9 · 2013: 10 · 2012: 11
- FWCI
- 2.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- FEBS Letters (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- MitoQ, mitochondria-targeted antioxidants, hydrophobicity tuning, triphenylphosphonium cation, ubiquinol, aliphatic chain length, partition coefficient, mitochondrial oxidative damage, membrane association
- MeSH terms
- Antioxidants, Biological Transport, Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone, Intracellular Membranes, Kinetics, Mitochondria, Models, Biological, Organophosphorus Compounds, Ubiquinone
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
