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Cited by 295Mitochondrial Function and PathologyCoenzyme Q10 studies and effectsParkinson's Disease Mechanisms and Treatments

Mitochondrial Approaches for Neuroprotection

Open access
Chaturvedi, Rajnish K., Beal, M. Flint·2008·Annals of the New York Academy of Sciences
DOI 10.1196/annals.1427.027PMC PMC2605644
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Abstract

A large body of evidence from postmortem brain tissue and genetic analysis in humans and biochemical and pathological studies in animal models (transgenic and toxin) of neurodegeneration suggest that mitochondrial dysfunction is a common pathological mechanism. Mitochondrial dysfunction from oxidative stress, mitochondrial DNA deletions, pathological mutations, altered mitochondrial morphology, and interaction of pathogenic proteins with mitochondria leads to neuronal demise. Therefore, therapeutic approaches targeting mitochondrial dysfunction and oxidative damage hold great promise in neurodegenerative diseases. This review discusses the potential therapeutic efficacy of creatine, coenzyme Q10, idebenone, synthetic triterpenoids, and mitochondrial targeted antioxidants (MitoQ) and peptides (SS‐31) in in vitro studies and in animal models of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We have also reviewed the current status of clinical trials of creatine, coenzyme Q10, idebenone, and MitoQ in neurodegenerative disorders. Further, we discuss newly identified therapeutic targets, including peroxisome proliferator‐activated receptor‐γ‐coactivator and sirtuins, which provide promise for future therapeutic developments in neurodegenerative disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that mitochondrial dysfunction and oxidative damage are common pathological mechanisms in Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. It evaluates mitochondria-targeted neuroprotective agents—including creatine, coenzyme Q10, idebenone, MitoQ, SS-31, and synthetic triterpenoids—and highlights PGC-1α and sirtuins as emerging therapeutic targets.

Key findings

  • Mitochondrial dysfunction is implicated across neurodegenerative diseases: complex-I inhibition by MPTP/rotenone in PD models; reduced complexes II–III and aconitase in HD; impaired TCA enzymes and respiratory complexes I, III, and IV in AD; and mutant SOD1-associated mitochondrial defects in ALS.
  • Creatine showed neuroprotection in multiple models, including MPTP-treated mice, G93A ALS mice, and R6/2 and N-171-82Q HD mice. In early PD, a phase II trial of creatine 10 g/day plus minocycline reported tolerability of 91% for creatine versus 77% for minocycline, and UPDRS progression slowed by almost 50% at 1 year compared with DATATOP controls; an NIH phase III trial planned to randomize 1720 participants to 10 g creatine or placebo. In HD, creatine 8 g/day for 16 weeks in 64 subjects was safe, bioavailable to brain, and decreased serum 8-hydroxy-2-deoxyguanosine.
  • CoQ10 at 360 mg/day reduced occipital cortex lactate concentrations by 37% in 18 HD patients. In the CARE-HD trial of 340 patients, CoQ10 600 mg/day produced a 14% decrease in disease progression over 30 months, while remacemide showed no efficacy. A phase II early-PD trial using 300, 600, or 1,200 mg/day for 16 months found a statistically significant dose-dependent reduction in UPDRS score; high doses up to 3,600 mg/day were safe, though plasma CoQ10 plateaued at 2,400 mg/day.
  • Mitochondrial-targeted agents showed preclinical promise: MitoQ entered a phase II PD trial; SS-31 at 5 mg/kg daily intraperitoneally from 30 days of age improved survival and motor performance in G93A ALS mice; CDDO-MA reduced MPTP and 3-NP toxicity; and PGC-1α and sirtuin/resveratrol pathways were protective in models of neurodegeneration.

Methods

  • Design: narrative review; no systematic review, meta-analysis, or formal search methodology is stated.
  • Data/sample: evidence from post-mortem human tissue, genetic analyses, in vitro cell models, transgenic and toxin animal models, and clinical trials in PD, HD, AD, and ALS.
  • Analysis: qualitative synthesis of preclinical and clinical findings for mitochondrial-targeted neuroprotective agents and emerging targets including PGC-1α and sirtuins.

Limitations

  • The paper states no explicit limitations.
  • Evident from the text: as a narrative review, it lacks systematic search criteria, inclusion/exclusion criteria, and quantitative synthesis.
  • Evident from the text: several cited findings are unpublished (e.g., Chaturvedi et al., Kipiani et al., Yang et al., Kiaei et al.), and clinical results for idebenone are described as controversial, with one large trial showing no benefit.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1196/annals.1427.027

Cites

312 of 312 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 132 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    A G11778A mtDNA point mutation in a subunit of mitochondrial complex-I was observed in a family with parkinsonism and multisystem degeneration.

    “We observed G11778A mtDNA point mutation in a subunit of mitochondrial complex-I in a family with parkinsonism and multisystem degeneration19.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Simon DK 1999 Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation Neurology 53 1787 93 10563629 source

      Not checked in the free run.

  • Findingcitation

    High levels of somatic mtDNA point mutations were identified in elderly PD patients.

    “We also identified high levels of somatic mtDNA point mutations in elderly PD patients20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Simon DK 2004 Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson's disease Neurobiol Aging 25 71 81 14675733 source

      Not checked in the free run.

  • Findingcitation

    CoQ10 had neuroprotective effects against DA depletion in the chronic MPTP model.

    “We found neuroprotective effects against DA depletion, loss of TH-IR neurons in the SN and the development of α–synuclein aggregates.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] Cleren C 2007 Therapeutic effects of coenzyme Q(10) (Q(10)) and reduced CoQ(10) in the MPTP model of Parkinsonism J Neurochem 17973981

      Not checked in the free run.

  • Findingcitation

    A combination of creatine and CoQ10 exerts synergistic neuroprotective effects in the MPTP model of PD.

    “Recently, we found that a combination of creatine and CoQ10 exerts synergistic neuroprotective effects in the MPTP model of PD (Yang et al., unpublished findings).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yang et al., unpublished findings

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  • Findingcitation

    CoQ10 provided significant protection against MPTP-induced dopamine depletion and loss of TH-IR neurons in aged mice.

    “We demonstrated CoQ10 provided significant protection against MPTP induced dopamine depletion and loss of TH-IR neurons in aged mice146.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Beal MF 1998 Coenzyme Q10 attenuates the 1-methyl-4-phenyl-1,2,3,tetrahydropyridine (MPTP) induced loss of striatal dopamine and dopaminergic axons in aged mice Brain Res 783 109 14 9479058 source

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  • May combine two claims. 41
  • Classified as probably not a substantial claim. 4

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    Findingown data

    Significantly reduced cellular respiration and COX activity were observed in myoblasts from HD patients, and these defects were exacerbated in chronic energy deprivation conditions.

    “We observed significantly reduced cellular respiration and COX activity in myoblasts from HD patients, and these defects were exacerbated in chronic energy deprivation conditions (Chaturvedi et. al., unpublished findings).”
    Quote in the paperNot a substantial claim

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    Findingown data

    Oral administration of creatine at a dose of 8 g/day for 16 weeks is well tolerated, safe and bioavailable to the brain, and it decreased serum 8-hydroxy-2-deoxyguanosine levels.

    “We found that oral administration of creatine at a dose of 8 g/day for 16 weeks is well tolerated, safe and bioavailable to the brain, and it decreased serum 8-hydroxy-2-deoxyguanosine levels, a marker for oxidative stress.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Hersch SM 2006 Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG Neurology 66 250 2 16434666 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    CoQ10 treatment decreases brain oxidative stress, Aβ42 levels, β-amyloid plaque area and number, and improves cognitive performance in Tg19959 mice, a transgenic mouse model of AD.

    “Recently, we found that CoQ10 treatment decreases brain oxidative stress, Aβ42 levels, β-amyloid plaque area and number, and improves cognitive performance in Tg19959 mice, a transgenic mouse model of AD (Kipiani et al., unpublished findings).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kipiani et al., unpublished findings

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    Findingcitation

    Creatine significantly improves survival, improves motor performance, slows the development of brain atrophy, increases brain ATP levels, delays atrophy of striatal neurons and the formation of Htt-positive aggregates in the R6/2 and N-171-82Q transgenic mouse models of HD.

    “We found that creatine significantly improves survival, improves motor performance, slows the development of brain atrophy, increases brain ATP levels, delays atrophy of striatal neurons and the formation of Htt-positive aggregates in the R6/2 and N-171-82Q transgenic mouse models of HD118-120.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [118] Andreassen OA 2001 Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington's disease Neurobiol Dis 8 479 91 11447996 source

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    • cites [119] Dedeoglu A 2003 Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington's disease transgenic mice J Neurochem 85 1359 67 12787055 PMC2866522 source

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    • cites [120] Ferrante RJ 2000 Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease J Neurosci 20 4389 97 10844007 PMC6772461 source

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  • May combine two claims.

    Findingown data

    Creatine produced protection against dopamine loss, as well as an attenuation of neuron loss in the substantia nigra of mice treated with MPTP.

    “We found that creatine produced protection against dopamine loss, as well as an attenuation of neuron loss in the SN of mice treated with MPTP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Oral administration of CoQ10 in PD patients was well tolerated and resulted in significant, dose-dependent increases in plasma CoQ10 levels.

    “In this study, oral administration of CoQ10 in PD patients was well tolerated and resulted in significant, dose-dependent increases in plasma CoQ10 levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [159] Shults CW 1997 Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects Ann Neurol 42 261 4 9266740 source

      Not checked in the free run.

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    Findingcitation

    Both SS-31 and SS-20 produce complete protection against MPTP neurotoxicity.

    “Both SS-31 and SS-20 also produce complete protection against MPTP neurotoxicity (Yang et al., unpublished findings).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yang et al., unpublished findings

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    Findingcitation

    CoQ10 levels are significantly reduced in mitochondria isolated from platelets of PD patients, directly correlated with a decrease in complex-I activity.

    “We found a significant reduction in CoQ10 levels in mitochondria isolated from platelets of PD patients, that directly correlated with a decrease in complex-I activity159.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [159] Shults CW 1997 Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects Ann Neurol 42 261 4 9266740 source

      Not checked in the free run.

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    Findingcitation

    CDDO-MA reduces t-butylhydroperoxide induced ROS generation, attenuates MPTP-induced nigrostriatal dopaminergic neurodegeneration and reduces 3-NP induced striatal lesions.

    “It reduces t-butylhydroperoxide induced ROS generation, attenuates MPTP-induced nigrostriatal dopaminergic neurodegeneration and reduces 3-NP induced striatal lesions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yang et al., unpublished findings

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  • May combine two claims.

    Interpretationreasoning

    Mitochondrial dysfunction due to oxidative stress, mitochondrial DNA deletions, pathological mutations, altered mitochondrial morphology and interaction of pathogenic proteins with mitochondria leads to neuronal demise.

    “Mitochondrial dysfunction due to oxidative stress, mitochondrial DNA deletions, pathological mutations, altered mitochondrial morphology and interaction of pathogenic proteins with mitochondria leads to neuronal demise.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a randomized, double-blind, Phase II futility clinical trial in early PD, creatine reduced UPDRS scores and could not be rejected as futile based on the 30% DATATOP futility threshold.

    “Creatine was shown to reduce the UPDRS scores, and could not be rejected as futile based on the 30% DATATOP futility threshold.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] 2006 A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease Neurology 66 664 71 16481597 source

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  • May combine two claims.

    Premisecitation

    Oral administration of creatine produces a dose-dependent improvement in motor performance and extends survival in G93A transgenic ALS mice, where it protects against loss of both motor neurons and SN neurons.

    “Oral administration of creatine produces a dose-dependent improvement in motor performance and extends survival in G93A transgenic ALS mice, where it protects against loss of both motor neurons and SN neurons114.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Klivenyi P 1999 Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis Nat Med 5 347 50 10086395 source

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  • May combine two claims.

    Interpretationreasoning
    § Mitochondrial approaches for neuroprotection

    Agents that alleviate mitochondrial dysfunction could be beneficial and exert neuroprotective effects in neurodegenerative disorders.

    “There is ample evidence showing involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders, therefore, one would predict that agents that alleviate mitochondrial dysfunction could be beneficial and exert neuroprotective effects.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mitochondrial dysfunction is a valid therapeutic target for neurodegenerative diseases.

  • May combine two claims.

    Premisecitation

    CoQ10 and remacemide combination therapy observed significantly improved motor performance and increased survival in the R6/2 and N-171-82Q transgenic mouse models of HD.

    “Similarly, we and others, by using CoQ10 and remacemide (NMDA antagonist) combination therapy observed significantly improved motor performance and increased survival in the R6/2 and the N-171-82Q transgenic mouse models of HD151, 154.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [151] Ferrante RJ 2002 Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease J Neurosci 22 1592 9 11880489 PMC6758854 source

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    • cites [154] Schilling G 2001 Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington's disease transgenic mouse model Neurosci Lett 315 149 53 11716985 source

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  • May combine two claims.

    Premisecitation

    Combination therapy of CoQ10 and minocycline in the R6/2 HD mouse model resulted in significantly increased amelioration of behavioral and neuropathological deficits, extended survival, improved rotarod performance and attenuated striatal neuron atrophy, as compared to either minocycline or CoQ10 alone.

    “The combination therapy of CoQ10 and minocycline in R6/2 transgenic mouse model of HD resulted in a significantly increased amelioration of behavioral and neuropathological deficits, extended survival, improved rotarod performance and attenuated striatal neuron atrophy, as compared to either minocycline or CoQ10 alone153.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] Stack EC 2006 Combination therapy using minocycline and coenzyme Q10 in R6/2 transgenic Huntington's disease mice Biochim Biophys Acta 1762 373 80 16364609 source

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    Premisecitation

    High-dose CoQ10 significantly extends survival, improves motor performance, grip strength and reduces brain atrophy in R6/2 HD mice, in a dose-dependent manner.

    “A dose ranging and efficacy study of highdose coenzyme Q10 formulations in the R6/2 HD transgenic mice demonstrated that high-dose CoQ10 significantly extends survival, improves motor performance, grip strength and reduces brain atrophy in R6/2 HD mice, in a dose-dependent manner152.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [152] Smith KM 2006 Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice Biochim Biophys Acta 1762 616 26 16647250 source

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    Premisecitation

    In two other clinical trials, idebenone was safe and tolerable up to 360 mg/day and slowed progression of cognitive deficits in patients with AD.

    “Subsequently, in two other clinical trials, idebenone was safe and tolerable up to 360 mg/day and slowed progression of cognitive deficits in patients with AD168, 169.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [168] Gutzmann H Hadler D 1998 Sustained efficacy and safety of idebenone in the treatment of Alzheimer's disease: update on a 2-year double-blind multicentre study J Neural Transm Suppl 54 301 10 9850939 source

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    • cites [169] Gutzmann H 2002 Safety and efficacy of idebenone versus tacrine in patients with Alzheimer's disease: results of a randomized, double-blind, parallel-group multicenter study Pharmacopsychiatry 35 12 8 11819153 source

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  • May combine two claims.

    Premisecitation

    Mitochondrial-targeted antioxidants including MitoQ and SS-31 play an important role in modulating ROS induced mitochondrial permeability transition and cell death, and were found to be protective in several in vitro and in vivo models of ischemia, reperfusion injury and neurodegeneration.

    “Mitochondrial-targeted antioxidants including mitochondrial CoQ10 (MitoQ) and Szeto-Schiller peptide (SS-31) play an important role in modulating ROS induced mitochondrial permeability transition and cell death, and were found to be protective in several in vitro and in vivo models of ischemia, reperfusion injury and neurodegeneration173.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [173] Armstrong JS 2007 Mitochondria-Directed Therapeutics. Antioxid Redox Signal 18092938

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  • May combine two claims.

    Interpretationreasoning

    These findings strongly support the notion that creatine, CoQ10 and idebenone are promising neuroprotective agents in debilitating neurodegenerative disorders.

    “These findings strongly support the notion that creatine, CoQ10 and idebenone are promising neuroprotective agents in debilitating neurodegenerative disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    SS-31 targeted to the inner mitochondrial membrane prevents apoptosis, necrosis, oxidative stress and inhibition of the mitochondrial electron transport chain.

    “Similarly, a novel peptide antioxidant (SS-31) targeted to the inner mitochondrial membrane prevents apoptosis, necrosis, oxidative stress and inhibition of the mitochondrial electron transport chain176.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [176] Szeto HH 2007 Mitochondria-Targeted Cytoprotective Peptides for Ischemia-Reperfusion Injury Antioxid Redox Signal 17999629

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    Premisecitation

    SS-31 protects neuronal cells against tert-butyl-hydroperoxide (tBHP) induced mitochondrial depolarization and apoptotic cell death by reducing intracellular ROS, decreasing markers of apoptotic cell death and caspase activity.

    “SS-31 protects neuronal cells against tert-butyl-hydroperoxide (tBHP) induced mitochondrial depolarization and apoptotic cell death by reducing intracellular ROS, decreasing markers of apoptotic cell death and caspase activity177.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [177] Zhao K 2005 Mitochondria-targeted peptide prevents mitochondrial depolarization and apoptosis induced by tert-butyl hydroperoxide in neuronal cell lines Biochem Pharmacol 70 1796 806 16216225 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The CARE-HD trial was powered to determine a 40% attenuation of total functional capacity decline with 80% power.

    “This trial was powered to be able to determine a 40% attenuation of total functional capacity decline with 80% power.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] 2001 A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease Neurology 57 397 404 11502903 source

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  • May combine two claims.

    Premisecitation

    MitoQ reduces ROS formation and preserves mitochondrial function after glutathione depletion, even in cells lacking mitochondrial DNA.

    “MitoQ reduces ROS formation and preserves mitochondrial function after glutathione depletion, even in the cells lacking mitochondrial DNA175.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Lu C 2007 Is Antioxidant Potential of the Mitochondrial Targeted Ubiquinone Derivative MitoQ Conserved in Cells Lacking mtDNA? Antioxid Redox Signal 17999633

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    Premisecitation

    MitoQ is a derivative of CoQ10 conjugated to triphenylalkylphosphonium ions, which promotes uptake into mitochondria, where it can combat ROS originating in mitochondria.

    “MitoQ is a derivative of CoQ10 conjugated to triphenylalkylphosphonium ions, which promotes uptake into mitochondria, where it can combat ROS originating in mitochondria174.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [174] Tauskela JS 2007 MitoQ--a mitochondria-targeted antioxidant IDrugs 10 399 412 17642004

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  • May combine two claims.

    Premisecitation

    The ratio of reduced to oxidized CoQ10 is significantly reduced in the platelets and cerebrospinal fluid of PD patients and in plasma of ALS patients.

    “The ratio of reduced to oxidized CoQ10 is significantly reduced in the platelets and cerebrospinal fluid (CSF) of PD patients156, 157 and in plasma of ALS patients158.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [156] Gotz ME 2000 Altered redox state of platelet coenzyme Q10 in Parkinson's disease J Neural Transm 107 41 8 10809402 source

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    • cites [157] Isobe C 2007 Increase of oxidized/total coenzyme Q-10 ratio in cerebrospinal fluid in patients with Parkinson's disease J Clin Neurosci 14 340 3 16647853 source

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    • cites [158] Sohmiya M 2005 An increase of oxidized coenzyme Q-10 occurs in the plasma of sporadic ALS patients J Neurol Sci 228 49 53 15607210 source

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  • May combine two claims.

    Premisecitation

    In a phase II clinical trial of CoQ10 in early PD, CoQ10 was safe and well tolerated at dosages up to 1200 mg/day.

    “CoQ10 was safe and well tolerated at dosages of up to 1200 mg/day and a statistically significant dose-dependent reduction in UPDRS score was evident in subjects assigned to CoQ10 compared to those assigned to placebo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] Shults CW 2002 Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline Arch Neurol 59 1541 50 12374491 source

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    Premisecitation

    Plasma CoQ10 levels reached a plateau at the 2400 mg/day dosage and did not increase further at the 3000 mg/day dosage in PD, HD or ALS patients.

    “However, plasma CoQ10 levels reached a plateau at the 2400 mg/day dosage and did not increase further at the 3000 mg/day dosage in PD, HD or ALS patients161, 162.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [161] Shults CW 2004 Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson's disease Exp Neurol 188 491 4 15246848 source

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    • cites [162] Ferrante KL 2005 Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS Neurology 65 1834 6 16344537 source

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    Premisecitation

    SS-31 prevents Ca2+ induced cytochrome c release and inhibits 3-NP-induced activation of the MPT pore and mitochondrial depolarization in isolated mitochondria.

    “SS-31 also prevents Ca2+ induced cytochrome c release and inhibits 3-NP-induced activation of the MPT pore and mitochondrial depolarization in isolated mitochondria178.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [178] Zhao K 2004 Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury J Biol Chem 279 34682 90 15178689 source

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  • May combine two claims.

    Premisecitation

    Following activation by TP, Nrf2 dissociates from Keap1, translocates to the nucleus, and binds to the ARE promoter sequences, leading to coordinated induction of a battery of cytoprotective genes including antioxidant and anti-inflammatory genes.

    “Following activation by TP, Nrf2 dissociates from Keap1, translocates to the nucleus, and binds to the ARE promoter sequences, leading to coordinated induction of a battery of cytoprotective genes including antioxidant and anti-inflammatory genes182.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [182] Lee JM 2005 Nrf2, a multi-organ protector? Faseb J 19 1061 6 15985529 source

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  • May combine two claims.

    Interpretationreasoning

    These studies suggest a potential neuroprotective effect of triterpenoids in cell and animal models of neurodegenerative disorders, and these compounds hold great promise as therapeutic agents for these disorders.

    “These studies suggest a potential neuroprotective effect of triterpenoids in cell and animal models of neurodegenerative disorders, and these compounds hold great promise as therapeutic agents for these disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In Nrf2 knockout mice, injection of 3-NP causes increased motor deficits and striatal lesions as compared to Nrf2+/+ mice, and these toxic effects of 3-NP were protected by adenoviral mediated over expression of Nrf2.

    “In the Nrf2 knockout (Nrf2−/−) mice, injection of the mitochondrial complex-II inhibitor 3-NP causes increased motor deficits and striatal lesions as compared to the Nrf2+/+ mice, and these toxic effects of 3-NP were protected by adenoviral mediated over expression of Nrf2185.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Shih AY 2005 Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo J Biol Chem 280 22925 36 15840590 source

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    Premisecitation

    Sirtuin activation improves mitochondrial function, extends lifespan, and promotes longevity in various species including yeast.

    “Sirtuin activation improves mitochondrial function, extends lifespan, and promotes longevity in various species including yeast193.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [193] Dali-Youcef N 2007 Sirtuins: the ‘magnificent seven’, function, metabolism and longevity Ann Med 39 335 45 17701476 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Synthetic TP compounds are potent inducers of the antioxidant response element (ARE)-Nrf2-Keap1 signaling pathway and are useful in a variety of cancers including leukemia, multiple myeloma, osteosarcoma, breast and lung cancer.

    “Synthetic TP compounds are potent inducers of the antioxidant response element (ARE)–Nrf2–Keap1 signaling pathway and are useful in a variety of the cancers including leukemia, multiple myeloma, osteosarcoma, breast and lung cancer181.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Liby KT Yore MM Sporn MB 2007 Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer Nat Rev Cancer 7 357 69 17446857 source

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  • May combine two claims.

    Premisecitation

    Synthetic triterpenoids (TP), analogues of oleanolic acid, are powerful inhibitors of oxidative stress and cellular inflammatory processes, and thus may be neuroprotective in neurodegeneration.

    “Synthetic triterpenoids (TP), analogues of oleanolic acid, are powerful inhibitors of oxidative stress and cellular inflammatory processes, and thus may be neuroprotective in neurodegeneration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [181] Liby KT Yore MM Sporn MB 2007 Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer Nat Rev Cancer 7 357 69 17446857 source

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  • May combine two claims.

    Premisecitation

    Nrf2 activator tert-butylhydroquinone has attenuated 3-NP toxicity in Nrf2+/+ mice, but not in Nrf2−/− mice.

    “Additionally, the Nrf2 activator tertbutylhydroquinone, has attenuated 3-NP toxicity in Nrf2+/+ mice, but not in Nrf2−/− mice185.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Shih AY 2005 Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo J Biol Chem 280 22925 36 15840590 source

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  • May combine two claims.

    Premisecitation

    Neuronal cultures derived from Nrf2 knockout mice show increased susceptibility to oxidative stress, as well as damage produced by mitochondrial electron transport chain complex inhibitors such as MPP+ and rotenone.

    “Neuronal cultures derived from the Nrf2 knockout mice show increased susceptibility to oxidative stress, as well as damage produced by mitochondrial electron transport chain complex inhibitors such as MPP+ and rotenone184.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [184] Lee JM 2003 NF-E2-related factor-2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons J Biol Chem 278 37948 56 12842875 source

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  • May combine two claims.

    Interpretationcitation

    These studies provide compelling evidence for a role of PGC-1α in the pathogenesis of neurodegenerative diseases, and thus it is a promising therapeutic target for neurodegenerative disorders.

    “These studies provide compelling evidence for a role of PGC-1α in the pathogenesis of neurodegenerative diseases, and thus it is a promising therapeutic target for neurodegenerative disorders2, 72.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Lin MT Beal MF 2006 Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases Nature 443 787 95 17051205 source

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    • cites [72] McGill JK Beal MF 2006 PGC-1alpha, a new therapeutic target in Huntington's disease? Cell 127 465 8 17081970 source

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  • May combine two claims.

    Interpretationreasoning

    Several agents, including creatine, CoQ10, MitoQ and idebenone are presently in clinical trials and show promising neuroprotective effects in these disorders.

    “Several agents, including creatine, CoQ10, MitoQ and idebenone are presently in clinical trials and show promising neuroprotective effects in these disorders.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Identification of new therapeutic targets including PGC-1α and Sirtuins may provide new avenues for therapy of neurodegenerative diseases.

    “Identification of new therapeutic targets including PGC-1α and Sirtuins may provide new avenues for therapy of neurodegenerative diseases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    SIRT-1 activation by resveratrol increases survival of motor neurons from transgenic ALS mice and reduces learning impairment and neurodegeneration in AD mouse models by decreasing acetylation of SIRT1 substrates PGC-1α and p53.

    “SIRT-1 activation by resveratrol increases survival of motor neurons from transgenic ALS mice and reduces learning impairment and neurodegeneration in AD mouse models by decreasing the acetylation of SIRT1 substrates PGC-1α and p53194.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [194] Kim D 2007 SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis Embo J 26 3169 79 17581637 PMC1914106 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Altogether, these studies provide strong evidence for involvement of Sirtuins in neuroprotection and targeting of Sirtuins could be an attractive therapeutic approach in neurodegenerative disorders.

    “Altogether, theses studies provide strong evidence for involvement of Sirtuins in neuroprotection and targeting of Sirtuins could be an attractive therapeutic approach in neurodegenerative disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Increased intracellular NAD+ concentration activates SIRT1 in brain following caloric restriction and this results in a reduction in amyloid pathology in a mouse model of Alzheimer disease.

    “Increased intracellular NAD+ concentration activates SIRT1 in brain following caloric restriction and this results in a reduction in amyloid pathology in a mouse model of Alzheimer disease197.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197] Qin W 2006 Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction J Biol Chem 281 21745 54 16751189 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Resveratrol in another study improved motor function in mice accompanied by a decrease in PGC1α acetylation leading to increased activity and mitochondrial biogenesis.

    “Similarly, resveratrol in another study improved motor function in mice which was accompanied by a decrease in PGC1α acetylation leading to increased activity and mitochondrial biogenesis196.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [196] Lagouge M 2006 Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha Cell 127 1109 22 17112576 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Therapeutic agents having the ability to target mitochondria and reduce mitochondrial dysfunction hold great promise for therapeutic interventions.

    “Therefore, therapeutic agents having the ability to target mitochondria and reduce mitochondrial dysfunction hold great promise for therapeutic interventions.”
    Quote in the paperNot a substantial claim
44 of 44

  • The paper relies on this without support.

    Animal model results for neuroprotective agents predict clinical efficacy in human neurodegenerative diseases.

    “The success of creatine in experimental studies led to clinical trials in neurodegenerative diseases including PD, HD and ALS.”

  • The paper relies on this without support.

    Mitochondrial dysfunction is a valid therapeutic target for neurodegenerative diseases.

    “There is ample evidence showing involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders, therefore, one would predict that agents that alleviate mitochondrial dysfunction could be beneficial and exert neuroprotective effects.”

  • The paper relies on this without support.

    Neuroprotective effects observed in animal models of neurodegenerative diseases predict neuroprotective efficacy in human patients.

    “On the basis of results from animal studies, we and others initiated several clinical trials of CoQ10 in neurodegenerative disorders.”

  • The paper relies on this without support.

    Plasma CoQ10 levels are a valid basis for selecting the dose for phase III clinical trials in HD.

    “This dose was chosen based on the studies of plasma CoQ10 concentrations discussed above.”
4 of 4

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?

Cites

1 retracted

Flagged first, then by citations

2 of the 314 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. 10.1002/1531-8249(200011)48:5<723::aid-ana5>3.0.co;2-w · DOI
  2. 10.1111/j.1471-4159.2005.03112.x · DOI · Paper page
  3. 10.1002/ana.410420221 · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Chaturvedi, R. K., & Beal, M. F.
Affiliations
Cornell University (US)
Corresponding author
  • Chaturvedi, Rajnish K.
  • Beal, M. Flint
ORCID
Venue
Annals of the New York Academy of Sciences
Publisher
Wiley
Published
2008-12
Volume
1147
Issue
1
Pages
395-412
ISSN
  • 0077-8923 (ISSN-L)
  • 1749-6632
DOI
10.1196/annals.1427.027
PMC
PMC2605644
OpenAlex
W2157205154
Cited by
294
References
314
Citations by year
2026: 8 · 2025: 10 · 2024: 13 · 2023: 17 · 2022: 14 · 2021: 10 · 2020: 12 · 2019: 9 · 2018: 13 · 2017: 9 · 2016: 11 · 2015: 15 · 2014: 21 · 2013: 15 · 2012: 27
FWCI
2.29
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 7 d)
Locations
  • Annals of the New York Academy of Sciences (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Neurological Disorders and Stroke (R01NS039258)
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
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
mitochondrial dysfunction, neuroprotection, neurodegenerative diseases, oxidative stress, mitochondrial DNA deletions, creatine, coenzyme Q10, idebenone, synthetic triterpenoids, MitoQ, SS-31, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, PPARγ coactivator, sirtuins, mitochondria-targeted antioxidants
MeSH terms
Animals, Humans, Mitochondria, Neuroprotective Agents, Neurodegenerative Diseases

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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.

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