The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index; 17 of the 26 sources its claims cite were checked for support.
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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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.
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Claims the paper makes
25 Own result · 20 Own interpretation · 7 Partly supported · 4 Supported · 4 No full text of the sources · 1 No basis given · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Introduction
What the sources say
- Partly supportedcites [17] Ross, 2008, Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochemical Journal sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [21] Millard, 2010, Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity, PLoS One sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Conclusion
What the sources say
- Partly supportedcites [17] Ross, 2008, Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochemical Journal sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [21] Millard, 2010, Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity, PLoS One sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [31] Asin-Cayuela, 2004, Fine-tuning the hydrophobicity of a mitochondria-targeted antioxidant, FEBS Letters source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Conclusion
What the sources say
- Partly supportedcites [30] Dranka, 2011, Assessing bioenergetic function in response to oxidative stress by metabolic profiling, Free Radical Biology and Medicine sourceExperimental — accuracy not yet measured
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)
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In the paper
“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].”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Introduction
What the sources say
- Partly supportedcites [17] Ross, 2008, Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochemical Journal sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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].”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Introduction
What the sources say
- Supportedcites [17] Ross, 2008, Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochemical Journal source
The Introduction states that TPP-cation uptake driven by membrane potential increases tenfold for every 61.5 mV at 37 °C. The Discussion confirms that uptake into mitochondria follows the Nernst equation, which applies to free, unbound cations. Page numbers were not provided in our copy. (LLM, conf=0.93)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Supported
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In the paper
“The hydrophobicity of the TPP+ compounds is an important factor controlling accumulation of the compounds.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Conclusion
What the sources say
- Supportedcites [17] Ross, 2008, Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochemical Journal source
The ‘Rapid and extensive uptake of MitoQ and DecylTPP by cells’ section reports that hydrophobic TPP compounds were taken up more rapidly and accumulated 4–10 times more extensively than the hydrophilic comparator TPMP. The Discussion also states that increasing hydrophobicity increased the rate of cellular uptake. Page numbers are not provided in our copy. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that all TPP+ compounds inhibited oxidative phosphorylation to different extents independent of the antioxidant functional groups.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Finally, MitoE was tested and was found to cause a progressive decrease in respiration following injection similar to TPMP (Figs. 5C, 3A).”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of adding an antioxidant functional group to alkyl TPP+ chain on cellular bioenergetics
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of adding an antioxidant functional group to alkyl TPP+ chain on cellular bioenergetics
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of adding an antioxidant functional group to alkyl TPP+ chain on cellular bioenergetics
plain- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 22
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In the paper
“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].”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Introduction
What the sources say
- Not checked — no full text of the sourcecites [8] Gane, 2008, 847 phase II study of the mitochondrial antioxidant mitoquinone for hepatitis C, Journal of Hepatology source
- Partly supportedcites [9] Fisher, 2009, Collagen fragmentation promotes oxidative stress and elevates matrix metalloproteinase-1 in fibroblasts in aged human skin, American Journal of Pathology sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [10] Adlam, 2005, Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury, FASEB Journal source
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [12] Orsucci, 2011, Targeting mitochondrial dysfunction and neurodegeneration by means of coenzyme Q10 and its analogues, Current Medicinal Chemistry source
- Partly supportedcites [13] Chacko, 2010, Prevention of diabetic nephropathy in Ins2(þ/)(AkitaJ) mice by the mitochondria-targeted therapy MitoQ, Biochemical Journal sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [14] Chacko, 2011, Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis, Hepatology sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Introduction
What the sources say
- Supportedcites [6] Murphy, 2008, Targeting lipophilic cations to mitochondria, Biochimica Biophysica Acta source
The Introduction states that lipophilic cations pass easily through lipid bilayers because their charge is dispersed over a large surface area, and describes their membrane-potential-driven uptake into cells and mitochondria. Section 4 explicitly says TPP cations pass easily through phospholipid bilayers. Together, these passages support membrane permeation without a specific uptake mechanism. (LLM, conf=0.91)
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- Supported
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In the paper
“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].”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Introduction
What the sources say
- Supportedcites [17] Ross, 2008, Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochemical Journal source
The Introduction identifies TPMP as a simple, hydrophilic TPP cation and reports that the more hydrophobic compounds MitoQ and DecylTPP enter cells more rapidly. The section on different uptake rates explains that this reflects faster passage across the plasma membrane, not faster transport across the mitochondrial membrane; thus the comparison supports slower net accumulation within cells. (LLM, conf=0.90)
- Partly supportedcites [21] Millard, 2010, Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity, PLoS One sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“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].”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Conclusion
What the sources say
- Supportedcites [17] Ross, 2008, Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells, Biochemical Journal source
The ‘Rapid and extensive uptake of MitoQ and DecylTPP by cells’ section reports that TPMP takes approximately 6–8 hours to reach steady-state uptake in cells; its FCCP results indicate mitochondrial-potential-dependent uptake. The ‘Biochemical’ section gives TPMP’s octan-1-ol/PBS partition coefficient as approximately 0.35. The comparison with respiratory inhibition shown in Fig. 4 is the citing authors’ interpretation, not a finding attributed to this source. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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].”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Introduction
What the sources say
- Not checked — no full text of the sourcecites [15] Nicholls, 2000, Mitochondrial membrane potential and neuronal glutamate excitotoxicity: mortality and millivolts, Trends in Neuroscience source
- Partly supportedcites [16] Nicholls, 2005, Commentary on: ‘old and new data, new issues: the mitochondrial Deltapsi’ by H. Tedeschi, Biochimica Biophysica Acta sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of lengthening the alkyl chain of TPP+ derivatives on cellular bioenergetics
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In the paper
“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.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of adding an antioxidant functional group to alkyl TPP+ chain on cellular bioenergetics
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“However, DTPP induced a rapid increase in basal ECAR and this was not further stimulated upon addition of oligomycin or FCCP (Fig. 4C).”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of lengthening the alkyl chain of TPP+ derivatives on cellular bioenergetics
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Consistent with inhibition of oxidative phosphorylation, MitoE caused an increase in glycolysis which was not further stimulated by oligomycin or FCCP injection (Fig. 6C).”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of adding an antioxidant functional group to alkyl TPP+ chain on cellular bioenergetics
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Surprisingly, oligomycin did not elicit a pronounced decrease in cellular respiration as expected nor did FCCP stimulate respiration.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of adding an antioxidant functional group to alkyl TPP+ chain on cellular bioenergetics
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Oligomycin caused a substantial decrease in OCR in control cells which was significantly suppressed by TPMP.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of lengthening the alkyl chain of TPP+ derivatives on cellular bioenergetics
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of adding an antioxidant functional group to alkyl TPP+ chain on cellular bioenergetics
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of lengthening the alkyl chain of TPP+ derivatives on cellular bioenergetics
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of lengthening the alkyl chain of TPP+ derivatives on cellular bioenergetics
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In the paper
“Lastly, injection of antimycin A significantly inhibited respiration in all groups with a significantly greater effect on the TPMP (1 μM) treated cells.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of lengthening the alkyl chain of TPP+ derivatives on cellular bioenergetics
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Conclusion
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In the paper
“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].”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Conclusion
What the sources say
- Not checked — no full text of the sourcecites [32] Doughan, 2007, Mitochondrial redox cycling of mitoquinone leads to superoxide production and cellular apoptosis, Antioxidants and Redox Signalling source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The effects of TPMP are to inhibit basal respiration but have a minimal effect on the maximal respiration.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of lengthening the alkyl chain of TPP+ derivatives on cellular bioenergetics
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of lengthening the alkyl chain of TPP+ derivatives on cellular bioenergetics
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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].”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Introduction
What the sources say
- Not checked — no full text of the sourcecites [19] Smith, 2004, Targeting coenzyme Q derivatives to mitochondria, Methods in Enzymology source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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In the paper
“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.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Introduction
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Conclusion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of adding an antioxidant functional group to alkyl TPP+ chain on cellular bioenergetics
“Interestingly, the respiratory response to the mitochondrial assay in MitoTempol treated cells was analogous to the response mediated by DTPP (Fig. 3B).”
§ Mitochondrially targeted compounds and their impact on cellular bioenergetics☆ > Results and discussion > The effects of lengthening the alkyl chain of TPP+ derivatives on cellular bioenergetics
“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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Metadata
- 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 › Neuroprotection in Cerebral Ischemia
- 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.
A language model drew the claims from the paper on 2026-11-02, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-02 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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 ›
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