Mitochondrially targeted compounds and their impact on cellular bioenergetics
Open accessAbstract
Mitochondria are recognized as critical sites of localized injury in a number of chronic pathologies which has led to the development of organelle directed therapeutics. One of the approaches employed to target molecules to the mitochondrion is to conjugate a delocalized cation such as triphenylphosphonium (TPP+) to various redox active compounds. Mitochondrially targeted antioxidants have also been used in numerous cell culture based studies as probes of the contribution of the mitochondrial generation of reactive oxygen species on cell signaling events. However, concentrations used in vitro are typically 10–100 times greater than those generated from oral dosing in a wide range of animal models and in humans. In the present study, we determined the effects of mitochondrial targeted antioxidants, MitoQ, MitoTempol, and MitoE on cellular bioenergetics of mesangial cells in culture and compared these to TPP+ conjugated compounds which lack the antioxidant functional group. We found that all TPP+ compounds inhibited oxidative phosphorylation to different extents independent of the antioxidant functional groups. These findings show that the TPP+ moiety can disrupt mitochondrial function at concentrations frequently observed in cell culture and this behavior is dependent on the linker group and independent of antioxidant properties. Moreover, the TPP+ moiety alone is unlikely to achieve the concentrations needed to contribute to the protective mechanisms of the mitochondrially targeted compounds that have been reported in vivo.
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Written from the paper’s full text.
TL;DR
Mitochondrially targeted TPP+ compounds inhibited oxidative phosphorylation in MES-13 cells at concentrations commonly used in culture, with effects dependent on the linker group and independent of antioxidant functional groups. The authors conclude that TPP+ itself can disrupt bioenergetics at concentrations unlikely to be achieved by oral dosing in vivo.
Key findings
- All TPP+ compounds inhibited oxidative phosphorylation to different extents independent of the antioxidant functional group; TPMP at 1 μM progressively decreased OCR, while 0.1 μM had no significant effect.
- Linker length mattered: 1 μM BTPP showed no changes in measured bioenergetic parameters, whereas 1 μM DTPP caused a transient decrease in basal OCR that reverted within 20 min and abolished the expected oligomycin response.
- MitoQ, MitoTempol, and MitoE at 1 μM each altered OCR/ECAR; MitoQ caused a steady decline in oxygen consumption over 2 h, and MitoTempol’s respiratory response was analogous to DTPP.
- Non-mitochondrially targeted Coenzyme Q10, Tempol, and Vitamin E had no effect on mitochondrial respiration (Table 1), while mitochondrially targeted antioxidants at 1 μM were significantly different from untreated controls (Table 2).
Methods
- Mouse kidney mesangial cells (MES-13) were seeded at 30,000 cells per well and assayed using a Seahorse XF-24 extracellular flux analyzer to measure OCR and ECAR simultaneously.
- TPP+ derivatives were injected individually at 0, 0.01, 0.1, or 1 μM, and bioenergetics were measured for 2 h followed by a mitochondrial function assay with oligomycin (1 μg/mL), FCCP (2 μM), and antimycin A (10 μM).
- Data are expressed as percentage of basal OCR or ECAR before injection; results are means±SEM (n=3–5 per group), analyzed by unpaired Student’s t test, ANOVA, and Newman–Keuls test with significance at P<0.05.
Limitations
- The paper states that effects of TPP+ compounds are likely dependent on cell type because cellular bioenergetics vary with mitochondrial number and regulation, and that cell culture conditions minimize metabolism and clearance of the drugs.
- The paper states that in vitro concentrations used are typically 10–100 times greater than those generated from oral dosing in animal models and humans, so the observed inhibition is unlikely to occur with therapeutic dosing.
- Evident from the text: the study uses a single cell line (MES-13) and focuses on acute 2 h exposures, so the findings may not generalize to other cell types or longer exposures.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
17 of 26 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The 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.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [17] Ross, 2008, Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochemical Journal source
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 measured - cites [21] Millard, 2010, Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity, PLoS One source
The Results section, “TP compounds localize to the mitochondria” (page unavailable), says the TPP moiety’s delocalized charge and lipophilic character favor mitochondrial accumulation, and reports mitochondrial localization of TP421. It does not say that the linker chain determines the extent of accumulation or compare accumulation across linker chains. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
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].”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [17] Ross, 2008, Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochemical Journal source
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 measured - cites [21] Millard, 2010, Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity, PLoS One source
The Results section, “TP compounds localize to the mitochondria” (page unavailable), reports uptake and mitochondrial localization of a TPP-containing compound. It does not examine whether retention or accumulation varies with the alkyl-chain length linking ubiquinol to TPP+; searches for chain length, linkers, and retention found no such comparison. (LLM, conf=0.79)
Experimental — accuracy not yet measured - cites [31] Asin-Cayuela, 2004, Fine-tuning the hydrophobicity of a mitochondria-targeted antioxidant, FEBS Letters source
- Interpretationcitation
The effects of TPP+ compounds are likely to be dependent on the cell type since the bioenergetics of cells show a wide range of responses depending on their number of mitochondria and regulation.
“The effects of TPP+ compounds is also likely to be dependent on the cell type since the bioenergetics of cells show a wide range of responses depending on their number of mitochondria and regulation [30].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [30] Dranka, 2011, Assessing bioenergetic function in response to oxidative stress by metabolic profiling, Free Radical Biology and Medicine source
In Protocol 1’s section on HNE responses in multiple cell types (page unavailable), the paper says the integrated bioenergetic response differs by cell type and reports different responses in myocytes, mesangial cells, and SH-SY5Y cells. That supports the cell-type rationale, but the passage concerns HNE, not TPP+ compounds, and does not attribute the differences to mitochondrial number or regulation. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
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].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [17] Ross, 2008, Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochemical Journal source
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 measured
- Premisecitation
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].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [17] Ross, 2008, Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochemical Journal source
- Premisecitation
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.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [17] Ross, 2008, Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochemical Journal source
- Findingown data
All TPP+ compounds inhibited oxidative phosphorylation to different extents independent of the antioxidant functional groups.
“We found that all TPP+ compounds inhibited oxidative phosphorylation to different extents independent of the antioxidant functional groups.”
Quote in the paperSubstantial claim - Findingown data
MitoE caused a progressive decrease in respiration following injection similar to TPMP.
“Finally, MitoE was tested and was found to cause a progressive decrease in respiration following injection similar to TPMP (Figs. 5C, 3A).”
Quote in the paperSubstantial claim - Findingown data
1 μM MitoQ caused a steady decline in oxygen consumption over 2 h.
“After the cells established a stable baseline, MitoQ was injected into the cellular media and caused a steady decline in oxygen consumption over 2 h.”
Quote in the paperSubstantial claim - Findingown data
Non-mitochondrially targeted compounds Coenzyme Q10, Tempol, and Vitamin E had no effect on mitochondrial respiration.
“In a separate series of experiments, it was determined that non-mitochondrially targeted compounds, Coenzyme Q10, Tempol, and Vitamin E had no affect on mitochondrial respiration (Table 1).”
Quote in the paperSubstantial claim - Findingown data
Antimycin A inhibited OCR to the same extent as controls in DTPP-treated cells.
“Antimycin A inhibited OCR to the same extent as controls indicating that these responses are mitochondrial in origin.”
Quote in the paperSubstantial claim - Findingown data
DTPP (1 μM) caused a transient decrease in basal OCR which reverted back to control levels within 20 min.
“DTPP (1 μM) caused a transient decrease in basal OCR which reverted back to control levels within 20 min (Fig. 3C).”
Quote in the paperNot a substantial claim - Findingown data
MitoTempol caused a steady increase in ECAR for 20 min before continuously declining over a 2 h period.
“As shown in Fig. 6B, MitoTempol caused a steady increase in ECAR for 20 min before continuously declining over a 2 h period.”
Quote in the paperNot a substantial claim - Findingown data
Antimycin A inhibited respiration to levels similar to control cells in MitoQ-treated cells.
“However, antimycin A inhibited respiration to levels similar to control cells.”
Quote in the paperSubstantial claim - Findingown data
The effects of the mitochondrially targeted antioxidants at higher concentrations (1 μM) were significantly different than untreated controls.
“However, the effects of the mitochondrially targeted antioxidants at higher concentrations (1 μM) were significantly different than untreated controls (Table 2).”
Quote in the paperSubstantial claim - Findingown data
Mitochondrial respiration was further inhibited to control levels with antimycin A injection in MitoTempol-treated cells.
“Mitochondrial respiration was further inhibited to control levels with antimycin A injection.”
Quote in the paperNot a substantial claim - Findingown data
Immediately upon addition of TPMP, ECAR increased such that the maximal level was reached approximately 1 h after its addition.
“Immediately upon addition of TPMP, ECAR increased such that the maximal level was reached approximately 1 h after its addition (Fig. 4A).”
Quote in the paperNot a substantial claim - Findingown data
The respiratory response to the mitochondrial assay in MitoTempol treated cells was analogous to the response mediated by DTPP.
“Interestingly, the respiratory response to the mitochondrial assay in MitoTempol treated cells was analogous to the response mediated by DTPP (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
BTPP had no effect on the cellular basal glycolytic rate.
“As shown in Fig. 4B, BTPP had no effect on the cellular basal glycolytic rate.”
Quote in the paperNot a substantial claim - Findingown data
MitoQ caused an initial transient increase in ECAR that returned back to basal levels within 2 h.
“MitoQ caused an initial transient increase in ECAR that returned back to basal levels within 2 h (Fig. 6A).”
Quote in the paperNot a substantial claim - Findingown data
Cells exposed to 1 μM BTPP showed no changes in any of the bioenergetic parameters measured compared to control cells.
“In contrast to TPMP, cells exposed to 1 μM BTPP showed no changes in any of the bioenergetic parameters measured compared to control cells (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
FCCP stimulation of respiration after oligomycin was substantially greater in the presence of 1 μM TPMP.
“Interestingly, the stimulation of respiration with FCCP after oligomycin was substantially greater in the presence of 1 μM TPMP.”
Quote in the paperNot a substantial claim - Premisecitation
Concentrations of mitochondrially targeted antioxidants used in vitro are typically 10-100 times greater than those generated from oral dosing in a wide range of animal models and in humans.
“However, concentrations used in vitro are typically 10–100 times greater than those generated from oral dosing in a wide range of animal models and in humans.”
- Also stated in: § Introduction · plain
“In the studies mentioned above, the concentrations of all of the mitochondrial targeted antioxidants were higher than those that can be achieved pharmacologically and associated with protective effects in vivo [26].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Rodriguez-Cuenca, 2010, Consequences of long-term oral administration of the mitochondria-targeted antioxidant MitoQ to wild-type mice, Free Radical Biology and Medicine source
- Also stated in: § Introduction · plain
- Interpretationreasoning
The TPP+ moiety alone is unlikely to achieve the concentrations needed to contribute to the protective mechanisms of mitochondrially targeted compounds that have been reported in vivo.
“Moreover, the TPP+ moiety alone is unlikely to achieve the concentrations needed to contribute to the protective mechanisms of the mitochondrially targeted compounds that have been reported in vivo.”
Quote in the paperSubstantial claim - Interpretationown data
The disruptive behavior of TPP+ compounds on mitochondrial function is dependent on the linker group.
“These findings show that the TPP+ moiety can disrupt mitochondrial function at concentrations frequently observed in cell culture and this behavior is dependent on the linker group and independent of antioxidant properties.”
Quote in the paperSubstantial claim - Interpretationown data
The TPP+ moiety can disrupt mitochondrial function at concentrations frequently observed in cell culture.
“These findings show that the TPP+ moiety can disrupt mitochondrial function at concentrations frequently observed in cell culture and this behavior is dependent on the linker group and independent of antioxidant properties.”
Quote in the paperSubstantial claim - Interpretationown data
The disruptive behavior of TPP+ compounds on mitochondrial function is independent of antioxidant properties.
“These findings show that the TPP+ moiety can disrupt mitochondrial function at concentrations frequently observed in cell culture and this behavior is dependent on the linker group and independent of antioxidant properties.”
Quote in the paperSubstantial claim - Interpretationreasoning
The rapid increase in ECAR by cells exposed to TPMP indicates activation of glycolysis to compensate for loss of mitochondrial ATP production.
“The rapid increase in ECAR by the cells exposed to TPMP indicates activation of glycolysis to compensate for loss of mitochondrial ATP production.”
Quote in the paperSubstantial claim - Interpretationown data
The responses to DTPP are mitochondrial in origin.
“Antimycin A inhibited OCR to the same extent as controls indicating that these responses are mitochondrial in origin.”
Quote in the paperSubstantial claim - Interpretationreasoning
The effects of TPMP on oxidative phosphorylation are reversible.
“Since FCCP will result in depolarization of the mitochondrial inner membrane and loss of TPMP from the mitochondrial matrix, it suggests the effects of TPMP on oxidative phosphorylation are reversible.”
Quote in the paperSubstantial claim - Interpretationown data
MitoQ disrupts the ability of the respiratory chain to transfer electrons to oxygen.
“Glycolysis increased minimally following oligomycin injection and was not further stimulated with FCCP or antimycin A treatment (Fig. 6A) suggesting that MitoQ is disrupting the ability of the respiratory chain to transfer electrons to oxygen.”
Quote in the paperSubstantial claim - Interpretationown data
The TPP+ group has a functional impact on cellular bioenergetics which is highly sensitive to the alkyl linker groups.
“It is clear from these data that the TPP+ group has a functional impact on cellular bioenergetics which is highly sensitive to the alkyl linker groups which have previously been assumed to be largely inert.”
Quote in the paperSubstantial claim - Premisecitation
The quantity of TPP+ conjugated compound found within mitochondria can vary substantially between different cell types because uptake depends on plasma and mitochondrial membrane potential, incubation volume, cell volume, and number of mitochondria.
“Because the extent of uptake of a TPP+ conjugated compound depends on the plasma and mitochondrial membrane potential, the volume of the incubation, the cell volume, and the number of mitochondria within a given cell, the quantity of the compound found within mitochondria can vary substantially between different cell types [18].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Smith, 2003, Delivery of bioactive molecules to mitochondria invivo, Proceedings of the National Academy of Sciences of the United States of America source
- Interpretationreasoning
Modifications to the linker, the mitochondrial targeting group, and the functional group are important in determining the biological properties of mitochondrially targeted compounds.
“Thus, it is increasingly clear that modifications to the linker, the mitochondrial targeting group, and the functional group are important in determining the biological properties of mitochondrially targeted compounds.”
Quote in the paperSubstantial claim - Interpretationown data
Based on our findings, it is likely that the majority of these effects can be ascribed to the non-specific effects of the TPP+ group on cellular bioenergetics.
“Based on our findings, it is likely that the majority of these effects can be ascribed to the non-specific effects of the TPP+ group on cellular bioenergetics.”
Quote in the paperSubstantial claim - Interpretationreasoning
Much of the effect of TPP+ compounds on cellular bioenergetics may be due to the increased extent of uptake of the TPP molecules when conjugated to a more hydrophobic carbon chain.
“Much of this effect may be due to the increased extent of uptake of the TPP molecules when conjugated to a more hydrophobic carbon chain.”
Quote in the paperSubstantial claim - Interpretationreasoning
The inhibition of oxidative phosphorylation achieved in cell culture by TPP+ conjugated compounds under conditions where metabolism and clearance of the drugs is minimal are extremely unlikely to occur with oral dosing in either animal models or human subjects.
“Importantly, the inhibition of oxidative phosphorylation achieved in cell culture by TPP+ conjugated compounds under conditions where metabolism and clearance of the drugs is minimal are extremely unlikely to occur with oral dosing in either animal models or human subjects.”
Quote in the paperSubstantial claim- Rests on an assumption: In cell culture, metabolism and clearance of the TPP+ conjugated drugs is minimal.
- Interpretationcitation
Mitochondrially targeted antioxidants may be clinically beneficial by preventing aberrant redox signaling and oxidative stress in the mitochondrion.
“These findings support the concept that mitochondrially targeted antioxidants may be clinically beneficial by preventing aberrant redox signaling and oxidative stress in the mitochondrion.”
Quote in the paperSubstantial claim - Interpretationown data
MitoTempol may be decreasing respiration in a similar manner as DTPP.
“These findings suggest that MitoTempol may be decreasing respiration in a similar manner as DTPP.”
Quote in the paperSubstantial claim
- May combine two claims. 22
May combine two claims.
PremisecitationMitoQ has been tested successfully in human diseases such as Hepatitis C induced liver disease and skin photo damage and in experimental animal models including ischemia-reperfusion, neurodegenerative diseases, diabetes, and alcohol-induced hepatosteatosis.
“For example, Mitoquinone (MitoQ) has been tested successfully in human diseases such as Hepatitis C induced liver disease and skin photo damage as well as a number of experimental animal models including ischemia-reperfusion, neurodegenerative diseases, diabetes, and alcohol-induced hepatosteatosis [8–14].”
Quote in the paperSubstantial claim4 of 7 sources checked- cites [8] Gane, 2008, 847 phase II study of the mitochondrial antioxidant mitoquinone for hepatitis C, Journal of Hepatology source
- cites [9] Fisher, 2009, Collagen fragmentation promotes oxidative stress and elevates matrix metalloproteinase-1 in fibroblasts in aged human skin, American Journal of Pathology source
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [10] Adlam, 2005, Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury, FASEB Journal source
- cites [11] Mitchell, 2011, The mitochondria-targeted antioxidant mitoquinone protects against cold storage injury of renal tubular cells and rat kidneys, Journal of Pharmacology and Experimental Therapeutics source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [12] Orsucci, 2011, Targeting mitochondrial dysfunction and neurodegeneration by means of coenzyme Q10 and its analogues, Current Medicinal Chemistry source
- cites [13] Chacko, 2010, Prevention of diabetic nephropathy in Ins2(þ/)(AkitaJ) mice by the mitochondria-targeted therapy MitoQ, Biochemical Journal source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [14] Chacko, 2011, Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis, Hepatology source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationTPP+ is a delocalized cation that is hydrophobic and can freely pass through phospholipid bilayers of the plasma membrane and other organelles without a specific uptake mechanism.
“This delocalized cation is hydrophobic and can freely pass through the phospholipid bilayers of the plasma membrane and other organelles, without the requirement for a specific uptake mechanism.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [6] Murphy, 2008, Targeting lipophilic cations to mitochondria, Biochimica Biophysica Acta source
May combine two claims.
PremisecitationTPMP 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].”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [17] Ross, 2008, Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochemical Journal source
- cites [21] Millard, 2010, Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity, PLoS One source
In Results, under “TP compounds localize to the mitochondria” (page unavailable), the paper says the triphenylphosphonium moiety’s lipophilic character favors mitochondrial accumulation. It does not identify TPMP or compare its hydrophobicity or accumulation rate with compounds having longer carbon linkers; its uptake measurement concerns TP421. (LLM, conf=0.76)
Experimental — accuracy not yet measured
May combine two claims.
InterpretationcitationTPMP 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].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [17] Ross, 2008, Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochemical Journal source
May combine two claims.
PremisecitationThe negative plasma membrane potential drives TPP+ movement from extracellular space into cytoplasm up to 10-fold, and TPP+ accumulates within mitochondria up to several hundred fold due to higher mitochondrial membrane potential.
“This is achieved because the cells’ negative plasma membrane potential (-30mV to -60mV) drives the movement of TPP+ from the extracellular space into the cytoplasmic compartment up to 10-fold. TPP+ can further accumulate within the mitochondria up to several hundred fold due to the higher mitochondrial membrane potential (−140 to −180 mV) [15,16].”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [15] Nicholls, 2000, Mitochondrial membrane potential and neuronal glutamate excitotoxicity: mortality and millivolts, Trends in Neuroscience source
- cites [16] Nicholls, 2005, Commentary on: ‘old and new data, new issues: the mitochondrial Deltapsi’ by H. Tedeschi, Biochimica Biophysica Acta source
The commentary’s discussion of lipophilic cations (section labeled Abstract; page unavailable) identifies TPP+ as a probe of mitochondrial membrane potential. It does not describe TPP+ moving from extracellular space into cytoplasm, or give the claimed plasma-membrane and mitochondrial potential ranges or 10-fold and several-hundred-fold accumulation figures. (LLM, conf=0.78)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataAddition of oligomycin to DTPP-treated cells did not elicit the anticipated decrease in OCR and further addition of FCCP resulted in an inhibition of respiration rather than a stimulatory response.
“However, addition of oligomycin did not elicit the anticipated decrease in OCR and further addition of FCCP resulted in an inhibition of respiration rather than a stimulatory response.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMitoTempol (1 μM) caused a progressive decline in mitochondrial respiration, which was later exacerbated with oligomycin and FCCP treatment.
“Following basal OCR readings, MitoTempol was added to the cells and caused a progressive decline in mitochondrial respiration, which was later shown to be exacerbated with oligomycin and FCCP treatment.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDTPP induced a rapid increase in basal ECAR and this was not further stimulated upon addition of oligomycin or FCCP.
“However, DTPP induced a rapid increase in basal ECAR and this was not further stimulated upon addition of oligomycin or FCCP (Fig. 4C).”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningMitoE caused an increase in glycolysis which was not further stimulated by oligomycin or FCCP injection.
“Consistent with inhibition of oxidative phosphorylation, MitoE caused an increase in glycolysis which was not further stimulated by oligomycin or FCCP injection (Fig. 6C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn MitoQ-treated cells, oligomycin did not elicit a pronounced decrease in cellular respiration as expected nor did FCCP stimulate respiration.
“Surprisingly, oligomycin did not elicit a pronounced decrease in cellular respiration as expected nor did FCCP stimulate respiration.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOligomycin caused a substantial decrease in OCR in control cells which was significantly suppressed by TPMP.
“Oligomycin caused a substantial decrease in OCR in control cells which was significantly suppressed by TPMP.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGlycolysis increased minimally following oligomycin injection and was not further stimulated with FCCP or antimycin A treatment in MitoQ-treated cells.
“Glycolysis increased minimally following oligomycin injection and was not further stimulated with FCCP or antimycin A treatment (Fig. 6A) suggesting that MitoQ is disrupting the ability of the respiratory chain to transfer electrons to oxygen.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTPMP at 0.1 μM had no significant effect on basal OCR whereas 1 μM TPMP progressively decreased OCR over a 2 h period.
“The lower concentration of TPMP (0.1 μM) had no significant affect on basal OCR whereas 1 μM TPMP progressively decreased OCR over a 2 h period.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn control cells, the maximum ECAR was elicited upon the addition of FCCP and this was not further increased in the TPMP (1 μM) treated cells.
“In the control cells, the maximum ECAR was elicited upon the addition of FCCP and this was not further increased in the TPMP (1 μM) treated cells.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAntimycin A significantly inhibited respiration in all groups with a significantly greater effect on TPMP (1 μM) treated cells.
“Lastly, injection of antimycin A significantly inhibited respiration in all groups with a significantly greater effect on the TPMP (1 μM) treated cells.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe alkyl TPP+ chain elicits cellular bioenergetic responses which are consistent with inhibition of oxidative phosphorylation and dependent on the length of the alkyl chain.
“Taken together, these data suggest that the alkyl TPP+ chain elicits cellular bioenergetic responses which are consistent with inhibition of oxidative phosphorylation and dependent on the length of the alkyl chain.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn bovine aortic endothelial cell isolated mitochondria, MitoQ induces superoxide, apoptosis, and redox cycling at complex I in a concentration and time dependent manner.
“In bovine aortic endothelial cell isolated mitochondria, MitoQ was shown to induce superoxide, apoptosis, and redox cycling at complex I in a concentration and time dependent manner [32].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [32] Doughan, 2007, Mitochondrial redox cycling of mitoquinone leads to superoxide production and cellular apoptosis, Antioxidants and Redox Signalling source
May combine two claims.
Interpretationown dataThe effects of TPMP are to inhibit basal respiration but have a minimal effect on the maximal respiration.
“The effects of TPMP are to inhibit basal respiration but have a minimal effect on the maximal respiration.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataDTPP rapidly cycles between the mitochondrial matrix and cytosol, thereby decreasing the control of respiration by the proton electrochemical potential gradient, effectively uncoupling mitochondria.
“In contrast, DTPP behaves quite differently in that oligomycin sensitivity is now completely diminished which is consistent with a rapid cycling of DTPP between the mitochondrial matrix and cytosol thereby decreasing the control of respiration by the proton electrochemical potential gradient, effectively uncoupling mitochondria.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe TPP+ moiety can have pharmacological or inhibitory properties due to its interactions with mitochondria, which can potentially be modified by both the linker group and the functional pharmacophores possessing antioxidant properties.
“The TPP+ moiety can also in principle have pharmacological or inhibitory properties due to its interactions with mitochondria which can potentially be modified by both the linker group and the functional pharmacophores possessing antioxidant properties [19].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Smith, 2004, Targeting coenzyme Q derivatives to mitochondria, Methods in Enzymology source
May combine two claims.
InterpretationreasoningEffects on cellular bioenergetics are consistently observed with TPP+ conjugated compounds but typically occur at concentrations at least one order of magnitude or greater than the levels associated with beneficial effects in disease models and are unlikely to contribute to the mechanism of action in vivo.
“Although effects on cellular bioenergetics are consistently observed with TPP+ conjugated compounds these typically occur at concentrations at least one order of magnitude or greater than the levels associated with beneficial effects in disease model and are unlikely to contribute to the mechanism of action in vivo.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningIn cell culture systems some of the bioenergetic and redox effects ascribed to the effects of mitochondrially targeted antioxidants are more likely due to the effects of the linker group and are evident only at concentrations which are not achieved in therapeutic dosing.
“In cell culture systems some of the bioenergetic and redox effects ascribed to the effects of mitochondrially targeted antioxidants are more likely due to the effects of the linker group and are evident only at concentrations which are not achieved in therapeutic dosing.”
Quote in the paperSubstantial claim
The paper relies on this without support.
In cell culture, metabolism and clearance of the TPP+ conjugated drugs is minimal.
“Importantly, the inhibition of oxidative phosphorylation achieved in cell culture by TPP+ conjugated compounds under conditions where metabolism and clearance of the drugs is minimal are extremely unlikely to occur with oral dosing in either animal models or human subjects.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
DTPP response is assigned to the BTPP figure panel
MinorThe text identifies Fig. 3B as the BTPP panel, but later cites Fig. 3B for the DTPP response.
“Interestingly, the respiratory response to the mitochondrial assay in MitoTempol treated cells was analogous to the response mediated by DTPP (Fig. 3B).”
“DTPP (1 μM) caused a transient decrease in basal OCR which reverted back to control levels within 20 min (Fig. 3C).”
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- Authors
- Reily, C., Mitchell, T., Chacko, B. K., Benavides, G. A., Murphy, M. P., & Darley-Usmar, V. M.
- Affiliations
- University of Alabama at Birmingham (US)
- MRC Mitochondrial Biology Unit (GB)
- Corresponding author
- Darley-Usmar, Victor M.
- ORCID
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2013
- Volume
- 1
- Issue
- 1
- Pages
- 86-93
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC3647698
- OpenAlex
- W2061982111
- Cited by
- 227
- References
- 32
- Citations by year
- 2026: 17 · 2025: 9 · 2024: 9 · 2023: 17 · 2022: 17 · 2021: 23 · 2020: 19 · 2019: 20 · 2018: 17 · 2017: 16 · 2016: 17 · 2015: 20 · 2014: 19 · 2013: 6
- FWCI
- 9.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (R01AA013395)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK075865, P30DK079337, T32DK007545, P30DK079626)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- triphenylphosphonium, mitochondrial bioenergetics, oxidative phosphorylation, MitoQ, mesangial cells, reactive oxygen species
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.
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Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-02.
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