Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells
Open accessAbstract
Mitochondria-targeted molecules comprising the lipophilic TPP (triphenylphosphonium) cation covalently linked to a hydrophobic bioactive moiety are used to modify and probe mitochondria in cells and in vivo. However, it is unclear how hydrophobicity affects the rate and extent of their uptake into mitochondria within cells, making it difficult to interpret experiments because their intracellular concentration in different compartments is uncertain. To address this issue, we compared the uptake into both isolated mitochondria and mitochondria within cells of two hydrophobic TPP derivatives, [3H]MitoQ (mitoquinone) and [3H]DecylTPP, with the more hydrophilic TPP cation [3H]TPMP (methyltriphenylphosphonium). Uptake of MitoQ by mitochondria and cells was described by the Nernst equation and was ∼5-fold greater than that for TPMP, as a result of its greater binding within the mitochondrial matrix. DecylTPP was also taken up extensively by cells, indicating that increased hydrophobicity enhanced uptake. Both MitoQ and DecylTPP were taken up very rapidly into cells, reaching a steady state within 15 min, compared with ∼8 h for TPMP. This far faster uptake was the result of the increased rate of passage of hydrophobic TPP molecules through the plasma membrane. Within cells MitoQ was predominantly located within mitochondria, where it was rapidly reduced to the ubiquinol form, consistent with its protective effects in cells and in vivo being due to the ubiquinol antioxidant. The strong influence of hydrophobicity on TPP cation uptake into mitochondria within cells facilitates the rational design of mitochondria-targeted compounds to report on and modify mitochondrial function in vivo.
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The extent of anchoring of TPP+ molecules to the inner mitochondrial membrane is dependent upon hydrophobicity, length of the linker unit, and functional group.
“The extent of anchoring of the TPP+ molecules to the inner mitochondrial membrane is dependent upon the hydrophobicity, the length of the linker unit, and the functional group [17].”
From Mitochondrially targeted compounds and their impact on cellular bioenergetics (2013) · cites this paper as [17]
The Discussion (page unavailable) reports extensive MitoQ binding within the mitochondrial matrix and says it is most likely bound to the matrix-facing surface of the inner membrane, with its hydrophobic side chain inserted into the membrane. The paper links hydrophobicity to uptake, but does not establish that the extent of inner-membrane anchoring depends on linker length or functional group. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRetention 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 [17]
The Results section ('Rapid and extensive uptake of MitoQ and DecylTPP by cells'; page unavailable) reports that these hydrophobic TPP compounds accumulate 4–10 times more extensively than hydrophilic TPMP, supporting a relationship between compound properties and accumulation. The paper does not compare different lengths of the alkyl chain linking ubiquinol to TPP+, or establish that retention depends on that chain length. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe physical properties of TPP+ conjugated compounds and the linker chain determine the extent of accumulation of the molecule within the mitochondria.
“It has been shown that the physical properties of the TPP+ conjugated compounds and the linker chain can also determine the extent of accumulation of the molecule within the mitochondria.”
From Mitochondrially targeted compounds and their impact on cellular bioenergetics (2013) · cites this paper as [17]
The Discussion (page unavailable) says that comparing hydrophobic TPP compounds with hydrophilic TPMP showed how hydrophobicity affects mitochondrial uptake, and the uptake results report greater accumulation of the hydrophobic compounds. The paper describes a ten-carbon chain in several compounds, but our copy does not show that it tested whether linker-chain properties independently determine the extent of accumulation. (LLM, conf=0.83)
Experimental — accuracy not yet measuredTPMP slowly accumulates into mitochondria within cells before reaching a steady state, which is consistent with the slow onset of inhibition of respiration.
“For instance, TPMP (octan-1-ol/PBS partition coefficient of 0.35) slowly accumulates into mitochondria within cells before reaching a steady state which is consistent with the slow onset of inhibition of respiration shown in Fig. 4 [17].”
From Mitochondrially targeted compounds and their impact on cellular bioenergetics (2013) · cites this paper as [17]
The hydrophobicity of TPP+ compounds is an important factor controlling accumulation of the compounds.
“The hydrophobicity of the TPP+ compounds is an important factor controlling accumulation of the compounds.”
From Mitochondrially targeted compounds and their impact on cellular bioenergetics (2013) · cites this paper as [17]
TPMP has relatively low hydrophobicity and slow rates of accumulation into mitochondria within cells compared to TPP+ molecules which are more hydrophobic due to longer carbon linkers.
“For example, triphenylmethylphosphonium (TPMP), a one carbon methyl attached to TPP+, has relatively low hydrophobicity and slow rates of accumulation into mitochondria within cells compared to TPP+ molecules which are more hydrophobic due to longer carbon linkers [17,21].”
From Mitochondrially targeted compounds and their impact on cellular bioenergetics (2013) · cites this paper as [17]
There is approximately tenfold accumulation of TPP+ within mitochondria for every ∼60 mV increase in mitochondrial membrane potential.
“It has been determined that there is an approximately tenfold accumulation of TPP+ within the mitochondria for every ∼60 mV increase in mitochondrial membrane potential [17].”
From Mitochondrially targeted compounds and their impact on cellular bioenergetics (2013) · cites this paper as [17]
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A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria
Hernansanz-Agustín, P., Morales-Vidal, C., Calvo, E., Natale, P., Martí-Mateos, Y., Jaroszewicz, S. N., Cabrera-Alarcón, J. L., Acín-Pérez, R., López-Montero, I., Vázquez, J., et al. (2024) · Cell · doi:10.1016/j.cell.2024.08.045 · Cited by 34 · see citing works
- Authors
- Ross, M. F., Prime, T. A., Abakumova, I., James, A. M., Porteous, C. M., Smith, R. A. J., & Murphy, M. P.
- Affiliations
- MRC Mitochondrial Biology Unit (GB)
- University of Otago (NZ)
- Corresponding author
- Abakumova, Irina
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2008-04-14
- Volume
- 411
- Issue
- 3
- Pages
- 633-645
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2010300252
- Cited by
- 206
- References
- 5
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 12 · 2023: 13 · 2022: 11 · 2021: 17 · 2020: 12 · 2019: 9 · 2018: 12 · 2017: 12 · 2016: 6 · 2015: 12 · 2014: 10 · 2013: 9 · 2012: 10
- FWCI
- 4.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion, other-oa)
- Funders
- Medical Research Council
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Keywords
- triphenylphosphonium cation, hydrophobicity, mitochondrial uptake, mitochondria-targeted compounds, MitoQ, plasma membrane transport, ubiquinol, mitochondrial antioxidants, Nernst equation
- MeSH terms
- Animals, Biological Transport, Cations, Cell Membrane, Fibroblasts, Humans, Mitochondria, Liver, Onium Compounds, Oxidation-Reduction, Time Factors, Triphenylmethyl Compounds, Molecular Structure, Jurkat Cells, Rats, Hydrophobic and Hydrophilic Interactions
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