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Cited by 1,011Redox biology and oxidative stressMitochondrial Function and PathologyCell death mechanisms and regulation

Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes

Open access
Hamanaka, Robert B., Chandel, Navdeep S.·2010·Trends in Biochemical Sciences
DOI 10.1016/j.tibs.2010.04.002PMC PMC2933303
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Abstract

Reactive oxygen species (ROS) have historically been viewed as toxic metabolic byproducts and causal agents in a myriad of human pathologies. More recent work, however, indicates that ROS are critical intermediates of cellular signaling pathways. Although it is clear that dedicated cellular ROS producers such as NADPH oxidases participate in signaling, evidence suggests that mitochondrial production of ROS is also a tightly controlled process, and plays a role in the maintenance of cellular oxidative homeostasis and propagation of cellular signaling pathways. Production of ROS at mitochondria thus integrates cellular energy state, metabolite concentrations, and other upstream signaling events and has important implications in cellular stress signaling, maintenance of stem cell populations, cellular survival, and oncogenic transformation.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that mitochondrial reactive oxygen species (ROS) are not merely toxic byproducts but regulated signaling intermediates that influence hypoxia responses, PI3K/Akt/FOXO signaling, stem cell maintenance, TNFα/NF-κB-mediated death, and oncogenic transformation. It proposes a hormetic model in which low ROS support proliferation/differentiation, moderate stress-induced ROS promote adaptation, and very high ROS cause senescence or death.

Key findings

  • Mitochondrial ROS are produced mainly as superoxide from electron transport chain complexes I, II, and III; complex III can release ROS on both sides of the inner membrane, and estimates suggest 0.15%–2% of cellular oxygen consumption results in superoxide in vitro, though in vivo production is unknown.
  • Hypoxia increases mitochondrial ROS, especially from complex III, and this ROS is required for HIF stabilization, AMPK/PKCζ-mediated Na/K-ATPase endocytosis, and pulmonary artery vasoconstriction; Na/K-ATPase can account for 20–80% of oxygen expenditure in mammalian cells.
  • PI3K-Akt activation increases mitochondrial ROS and inhibits FOXO-dependent expression of SOD2 and catalase, while FOXO activity supports antioxidant defense, stem cell maintenance, and protection against cardiac hypertrophy.
  • Mitochondrial ROS contribute to transformation: Sirt3−/− fibroblasts accumulate mitochondrial ROS and become transformed with either Myc or Ras alone, whereas wild-type cells require both oncogenes; SOD2 expression inhibits this transformation.

Methods

  • Narrative review synthesizing published literature on mitochondrial ROS production and ROS-dependent signaling pathways.
  • No primary experimental data are presented; the paper discusses studies in cell lines, mouse models, Drosophila, and C. elegans.
  • Main analysis is conceptual synthesis, including a proposed hormetic model of mitochondrial ROS in cellular and organismal fitness.

Limitations

  • The paper states that in many pathways direct biochemical evidence for ROS involvement has yet to be provided, and that little is known about mitochondrial function and superoxide production in vivo.
  • The paper states that the mechanism of hypoxic induction of mitochondrial ROS remains unclear, including whether it is intrinsic to mitochondria or requires other cellular factors.
  • As evident from the text, this is a review rather than a systematic review or primary study, so it does not provide new quantitative data or formal risk-of-bias assessment.

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

Integrity signals

Registry

Crossref · 10.1016/j.tibs.2010.04.002

Cites

99 of 99 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 167 cited sources checked · 0 supported · 0 flagged

  • Interpretationnone given
    § Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes

    Mitochondrial production of ROS is a tightly controlled process.

    “evidence suggests that mitochondrial production of ROS is also a tightly controlled process”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Between 0.15% and 2% of cellular oxygen consumption results in superoxide, based on in vitro measurements.

    “Several groups have measured the rate of mitochondrial superoxide production in vitro, leading to the estimation that between 0.15% and 2% of cellular oxygen consumption results in superoxide 2, 5.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Murphy, 2009, How mitochondria produce reactive oxygen species, Biochem. J. source

      Not checked in the free run.

    • cites [5] Brand, M.D. The sites and topology of mitochondrial superoxide production. Exp Gerontol, in press

      Not checked in the free run.

  • Premisecitation

    For a given cell, the rate of ROS production from the electron transport chain varies with the amount of electron carriers present in a state capable of reacting with O2.

    “For a given cell, the rate of ROS production from the electron transport chain varies with the amount of electron carriers present in a state capable of reacting with O2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Murphy, 2009, How mitochondria produce reactive oxygen species, Biochem. J. source

      Not checked in the free run.

  • Interpretationnone given
    § Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes

    Production of ROS at mitochondria integrates cellular energy state, metabolite concentrations, and other upstream signaling events.

    “Production of ROS at mitochondria thus integrates cellular energy state, metabolite concentrations, and other upstream signaling events”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Hypoxia leads to an increase in mitochondrial production of ROS.

    “Paradoxically, hypoxia leads to an increase in mitochondrial production of ROS.”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [8] Chandel, 1998, Mitochondrial reactive oxygen species trigger hypoxia-induced transcription, Proc. Natl. Acad. Sci. U. S. A. source

      Not checked in the free run.

    • cites [9] Waypa, 2001, Model for hypoxic pulmonary vasoconstriction involving mitochondrial oxygen sensing, Circ. Res. source

      Not checked in the free run.

    • cites [10] Bell, 2007, Mitochondrial reactive oxygen species trigger hypoxia-inducible factor-dependent extension of the replicative life span during hypoxia, Mol. Cell. Biol. source

      Not checked in the free run.

    • cites [11] Chandel, 2000, Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing, J. Biol. Chem. source

      Not checked in the free run.

    • cites [12] Dada, 2003, Hypoxia-induced endocytosis of Na,K-ATPase in alveolar epithelial cells is mediated by mitochondrial reactive oxygen species and PKC-zeta, J. Clin. Invest. source

      Not checked in the free run.

    • cites [13] Emerling, 2009, Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio, Free Radic. Biol. Med. source

      Not checked in the free run.

    • cites [14] Waypa, 2006, Increases in mitochondrial reactive oxygen species trigger hypoxia-induced calcium responses in pulmonary artery smooth muscle cells, Circ. Res. source

      Not checked in the free run.

  • May combine two claims. 36
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Interpretationreasoning
    § Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes

    Mitochondrial ROS production plays a role in the maintenance of cellular oxidative homeostasis and in the propagation of cellular signaling pathways.

    “and plays a role in the maintenance of cellular oxidative homeostasis and propagation of cellular signaling pathways”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Mitochondria are a principal source of cellular reactive oxygen species.

    “Mitochondria are a principal source of cellular reactive oxygen species (ROS).”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Superoxide is converted to hydrogen peroxide by superoxide dismutases both within mitochondria and in the cytosol.

    “Superoxide is the proximal ROS produced by mitochondria and is converted to hydrogen peroxide (H2O2) through the action of superoxide dismutases (SODs) both within the mitochondria and in the cytosol.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    AMPK phosphorylation of the tuberous sclerosis complex during hypoxia leads to inhibition of mTOR activity and conservation of cellular energy by inhibiting protein translation.

    “This leads to inhibition of mTOR activity and further conservation of cellular energy by inhibiting the energetically-costly process of protein translation 24.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Liu, 2006, Hypoxia-induced energy stress regulates mRNA translation and cell growth, Mol. Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Akt positively regulates mTOR, which is a key regulator of mitochondrial oxygen consumption and oxidative capacity.

    “Akt positively regulates the mammalian target of rapamycin (mTOR), which is a key regulator of mitochondrial oxygen consumption and oxidative capacity 29.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Schieke, 2006, The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity, J. Biol. Chem. source

      Not checked in the free run.

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    Premisecitation

    Activation of phosphoinositide-3-kinase by ligation of growth factors to their cellular receptors promotes recruitment of Akt to the plasma membrane and its subsequent activation.

    “Activation of phosphoinositide-3-kinase (PI3K) by ligation of growth factors to their cellular receptors promotes recruitment of Akt to the plasma membrane and its subsequent activation 28.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Cantley, 2002, The phosphoinositide 3-kinase pathway, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ρ0 Hep3B cells do not contain mitochondrial DNA and demonstrate no electron transport or ROS production.

    “These cells do not contain mitochondrial DNA and thus demonstrate no electron transport or ROS production”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Chandel, 1998, Mitochondrial reactive oxygen species trigger hypoxia-induced transcription, Proc. Natl. Acad. Sci. U. S. A. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Complex III accepts electrons donated to coenzyme Q by mitochondrial complexes I and II and transfers them to cytochrome c.

    “Complex III accepts electrons donated to coenzyme Q by mitochondrial complexes I and II and transfers them to cytochrome c.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Genetic targeting of the complex III subunit Rieske iron-sulfur protein abolishes ROS formation during hypoxia, preventing activation of downstream signaling effectors.

    “Thus, genetic targeting of the complex III subunit Rieske iron-sulfur protein, the protein required for electron transfer from ubiquiol, abolishes ROS formation during hypoxia, preventing the activation of downstream signaling effectors 17, 19, 20.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Brunelle, 2005, Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation, Cell Metab. source

      Not checked in the free run.

    • cites [19] Guzy, 2005, Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing, Cell Metab. source

      Not checked in the free run.

    • cites [20] Bell, 2007, The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production, J. Cell Biol. source

      Not checked in the free run.

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

    Premisereasoning

    The hydroxylation reaction that targets HIF-α subunits is carried out by prolyl hydroxylases 1, 2, and 3.

    “This hydroxylation reaction is carried out by a family of 2-oxoglutarate-dependent dioxygenases termed prolyl hydroxylases 1, 2, and 3 (PHD1-3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Induction of FOXO3a activity during the hypertrophic response increases mitochondrial ROS scavenging, attenuating pro-growth signaling and protecting cardiomyocytes from prolonged hypertrophic growth.

    “Induction of FOXO3a activity during the hypertrophic response thus increases mitochondrial ROS scavenging, attenuating pro-growth signaling and protecting cardiomyocytes from prolonged hypertrophic growth 40.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Sundaresan, 2009, Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice, J. Clin. Invest.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cells expressing a mutant cytochrome b subunit are unable to consume oxygen for oxidative phosphorylation but are able to produce complex III-derived ROS and stabilize HIF during hypoxia.

    “Thus, cells that express a mutant cytochrome b subunit are unable to consume oxygen for oxidative phosphorylation, but are able to produce complex III-derived ROS and stabilize HIF during hypoxia 20.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Bell, 2007, The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production, J. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Hypoxia induces ROS production from mitochondrial complex III, creating a cytosolic signal that stabilizes HIF.

    “Further experiments using mitochondrial inhibitors, antioxidants, and genetic targeting of mitochondrial proteins suggested that hypoxia induces ROS production from mitochondrial complex III, creating a cytosolic signal that stabilizes HIF 11, 17–19.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [11] Chandel, 2000, Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing, J. Biol. Chem. source

      Not checked in the free run.

    • cites [17] Brunelle, 2005, Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation, Cell Metab. source

      Not checked in the free run.

    • cites [18] Mansfield, 2005, Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation, Cell Metab. source

      Not checked in the free run.

    • cites [19] Guzy, 2005, Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    At the organismal level, mitochondrial ROS regulate airway fluid absorption and oxygen exchange in the pulmonary vasculature.

    “At the organismal level, mitochondrial ROS regulate airway fluid absorption and oxygen exchange in the pulmonary vasculature.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The increase in calcium and subsequent pulmonary artery vasoconstriction are both dependent on hypoxic mitochondrial ROS production.

    “This increase in calcium and subsequent pulmonary artery vasoconstriction are both dependent on hypoxic mitochondrial ROS production 9, 14.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Waypa, 2001, Model for hypoxic pulmonary vasoconstriction involving mitochondrial oxygen sensing, Circ. Res. source

      Not checked in the free run.

    • cites [14] Waypa, 2006, Increases in mitochondrial reactive oxygen species trigger hypoxia-induced calcium responses in pulmonary artery smooth muscle cells, Circ. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Akt activation is associated with increased oxygen consumption and an increase in total cellular ATP derived from both glycolytic and oxidative sources.

    “Akt activation is associated with increased oxygen consumption as well as an increase in total cellular ATP derived from both glycolytic and oxidative sources 30, 31.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [30] Gottlob, 2001, Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase, Genes Dev. source

      Not checked in the free run.

    • cites [31] Nogueira, 2008, Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis, Cancer Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The unpaired electron of ubisemiquinone is normally transferred to the cytochrome b center of complex III, but can also react with molecular oxygen to form superoxide.

    “Normally, the unpaired electron of ubisemiquinone is transferred to the cytochrome b center of complex III; however, this electron can also react with molecular oxygen to form superoxide 2, 26.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Murphy, 2009, How mitochondria produce reactive oxygen species, Biochem. J. source

      Not checked in the free run.

    • cites [26] Turrens, 1985, Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria, Arch. Biochem. Biophys. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Activation of the PI3K-Akt pathway results in increased production of ROS from mitochondria through metabolic pathways and in the inability to scavenge mitochondrial ROS through inhibition of FOXOs.

    “Thus, activation of the PI3K-Akt pathway not only results in increased production of ROS from mitochondria through metabolic pathways, but also the inability to scavenge mitochondrial ROS through inhibition of FOXOs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Atm deficiency leads to increased cellular ROS levels in hematopoietic stem cells, resulting in activation of p38 MAPK and mitotic entry.

    “Atm deficiency leads to increased cellular ROS levels in HSCs, resulting in activation of p38 mitogen-activated protein kinase (MAPK) and mitotic entry”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Ito, 2006, Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells, Nat. Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    SOD2 provides a protective effect by lowering cellular ROS levels and decreasing JNK activation after TNFα treatment.

    “SOD2 provides a protective effect by lowering cellular ROS levels and decreasing JNK activation after TNFα treatment 53.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Kamata, 2005, Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases, Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Treatment of cells with TNFα leads to mitochondrial ROS production, oxidation of JNK phosphatase catalytic cysteines, and activation of JNK signaling and cell death.

    “Treatment of cells with TNFα thus leads to mitochondrial ROS production, oxidation of JNK phosphatase catalytic cysteines, and activation of JNK signaling and cell death.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Oxidation of the cysteine sulfhydryl group can alter protein-protein interactions, the DNA binding activity of transcription factors, and the catalytic activity of enzymes.

    “Oxidation of the cysteine sulfhydryl group can alter protein–protein interactions, the DNA binding activity of transcription factors, and the catalytic activity of enzymes.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Cellular transformation is a multistep process requiring acquisition of activated oncogenes and loss of tumor-suppressor genes, leading to usurpation of cellular signaling pathways controlling proliferation, survival, and metabolism.

    “Cellular transformation is a multistep process requiring acquisition of activated oncogenes and loss of tumor-suppressor genes, leading to usurpation of cellular signaling pathways controlling proliferation, survival, and metabolism 65, 66.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [65] Hahn, 2002, Rules for making human tumor cells, N. Engl. J. Med. source

      Not checked in the free run.

    • cites [66] Jones, 2009, Tumor suppressors and cell metabolism: a recipe for cancer growth, Genes Dev. source

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  • May combine two claims.

    Premisecitation

    Overproduction of mitochondrial ROS leads to precocious differentiation into mature blood cells, whereas increased scavenging ability inhibits differentiation.

    “overproduction of mitochondrial ROS leads to precocious differentiation into mature blood cells whereas increased scavenging ability inhibits differentiation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Owusu-Ansah, 2009, Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The low pKa of the catalytic cysteine allows it to act as a nucleophile for catalysis of dephosphorylation but also makes it a target for oxidation by ROS.

    “The low pKa of this cysteine allows it to act as a nucleophile for catalysis of the dephosphorylation reaction, but also makes it a target for oxidation by ROS 6, 7.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Janssen-Heininger, 2008, Redox-based regulation of signal transduction: principles, pitfalls, and promises, Free Radic. Biol. Med. source

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    • cites [7] Brandes, 2009, Thiol-based redox switches in eukaryotic proteins, Antioxid. Redox Signal. source

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  • May combine two claims.

    Premisecitation

    The outcome of TNFα exposure on cell fate depends on the activities of two separate TNFR complexes, one of which mediates survival through activation of NF-κB.

    “The outcome of TNFα exposure on cell fate depends on the activities of two separate TNFR complexes, one of which mediates survival through activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) 55.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Micheau, 2003, Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes, Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Low levels of ROS are required for quiescence and stem cell maintenance, whereas ROS induction leads to proliferation and differentiation programs.

    “Low levels of ROS are required for quiescence and stem cell maintenance, whereas ROS induction leads to proliferation and differentiation programs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cells without intact NF-κB lack SOD2 induction and accumulate ROS at much higher levels than wild-type cells when treated with TNFα, corresponding with increased JNK activation.

    “Cells without intact NF-κB lack SOD2 induction and accumulate ROS at much higher levels than their wild-type counterparts when treated with TNFα, corresponding with increased JNK activation 53, 60.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [53] Kamata, 2005, Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases, Cell source

      Not checked in the free run.

    • cites [60] Sakon, 2003, NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death, EMBO J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of oncogenes, aberrant metabolism, mitochondrial dysfunction, and loss of the tumor suppressor p53 can all promote increased ROS accumulation in cancer cells.

    “Activation of oncogenes, aberrant metabolism, mitochondrial dysfunction, and loss of the tumor suppressor p53 can all promote increased ROS accumulation in cancer cells 69.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Trachootham, 2009, Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?, Nat. Rev. Drug Discov. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Elevated ROS levels are required for tumor growth and can promote transformation, even acting as the "second hit" in the Knudson two-hit model of carcinogenesis.

    “The available data suggests that elevated ROS levels are required for tumor growth and can promote transformation, even acting as the “second hit” in the Knudson two-hit model of carcinogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The G13997A mutation in the gene encoding the ND6 subunit of mitochondrial complex I is associated with high HIF activity and increased metastatic potential.

    “This mutation is also associated with high HIF activity and increased metastatic potential 76, 77.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [76] Ishikawa, 2008, ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis, Science source

      Not checked in the free run.

    • cites [77] Koshikawa, 2009, Reactive oxygen species-generating mitochondrial DNA mutation up-regulates hypoxia-inducible factor-1alpha gene transcription via phosphatidylinositol 3-kinase-Akt/protein kinase C/histone deacetylase pathway, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sirt3−/− cells become transformed after expression of either Myc or Ras, whereas wild-type cells require expression of both oncogenes.

    “Sirt3−/− cells become transformed after expression of either Myc or Ras, whereas wild-type cells require expression of both oncogenes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Kim, H.S. et al. SIRT3 Is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17, 41–52 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The ROS accumulation in Sirt3−/− fibroblasts is associated with decreased flux through mitochondrial complexes I and III and reduced cellular levels of SOD2.

    “This ROS accumulation is associated with decreased flux through mitochondrial complexes I and III (possibly allowing for increased escape of electrons to O2), and reduced cellular levels of SOD2 72.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Kim, H.S. et al. SIRT3 Is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17, 41–52 source

      Not checked in the free run.

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

    Premisecitation

    High cellular ROS levels are associated with cancer, diabetes, inflammatory diseases, ischemia-related diseases, and neurodegeneration.

    “Second, high cellular ROS levels are associated with cancer, diabetes, inflammatory diseases, ischemia-related diseases, and neurodegeneration, and are thus commonly thought to contribute to human pathologies and aging 80–83.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [80] Finkel, 2007, The common biology of cancer and ageing, Nature source

      Not checked in the free run.

    • cites [81] Lin, 2006, Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases, Nature source

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    • cites [82] Brownlee, 2001, Biochemistry and molecular cell biology of diabetic complications, Nature source

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    • cites [83] Nathan, 2002, Points of control in inflammation, Nature source

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

    Premisenone given

    Transformed cells acquire capabilities such as anchorage-independent growth, limitless proliferation, and evasion of apoptotic signals.

    “Transformed cells acquire capabilities such as anchorage-independent growth, limitless proliferation, and evasion of apoptotic signals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Clinical trials using antioxidants to scavenge ROS have consistently failed, and in some cases, actually increased mortality.

    “This line of thinking has led to multiple clinical trials using antioxidants to scavenge ROS, yet these trials have consistently failed, and in some cases, actually increased mortality 84–87.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [84] Storch, 2007, Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease, Arch. Neurol. source

      Not checked in the free run.

    • cites [85] Kang, 2009, Vitamin E, vitamin C, beta carotene, and cognitive function among women with or at risk of cardiovascular disease: the Women's Antioxidant and Cardiovascular Study, Circulation source

      Not checked in the free run.

    • cites [86] Lin, 2009, Vitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trial, J. Natl. Cancer Inst. source

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    • cites [87] Bjelakovic, 2007, Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis, J. Am. Med. Assoc. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Depending on the level of transgene expression, Sod2 transgenic mice display growth retardation and decreased fertility.

    “depending on the level of transgene expression, these mice display growth retardation and decreased fertility 90, 91.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [90] Van Remmen, 2003, Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging, Physiol. Genomics source

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    • cites [91] Raineri, 2001, Strain-dependent high-level expression of a transgene for manganese superoxide dismutase is associated with growth retardation and decreased fertility, Free Radic. Biol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SIRT3 is present in mitochondria, where it regulates the acetylation and activity of a variety of metabolic enzymes.

    “Interestingly, SIRT3 is present in mitochondria, where it regulates the acetylation and activity of a variety of metabolic enzymes, suggesting additional ways that it might affect mitochondrial ROS production 73.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Hirschey, M.D. et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cells harboring the G13997A mutation in the gene encoding the ND6 subunit of mitochondrial complex I are characterized by respiratory deficiency and high ROS production.

    “Cells harboring the G13997A mutation in the gene encoding the ND6 subunit of mitochondrial complex I are characterized by respiratory deficiency and high ROS production.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [76] Ishikawa, 2008, ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis, Science source

      Not checked in the free run.

    • cites [77] Koshikawa, 2009, Reactive oxygen species-generating mitochondrial DNA mutation up-regulates hypoxia-inducible factor-1alpha gene transcription via phosphatidylinositol 3-kinase-Akt/protein kinase C/histone deacetylase pathway, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Cellular stress can cause increased ROS levels, which can promote adaptation and possibly organismal fitness.

    “Cellular stress can cause increased ROS levels, which can promote adaptation and possibly organismal fitness.”
    Quote in the paperSubstantial claim
40 of 40

  • The paper relies on this without support.

    The failure of clinical trials using antioxidants to scavenge ROS is due to the inadequacy of the damaging-only view of ROS rather than other factors.

    “This line of thinking has led to multiple clinical trials using antioxidants to scavenge ROS, yet these trials have consistently failed, and in some cases, actually increased mortality 84–87.”
1 of 1

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?

  • Intracellular ROS changes might control whether HSCs and possibly other adult stem cells stay quiescent or proliferate.

    “Changes in intracellular levels of ROS may also determine the balance between quiescence and proliferation of HSCs, and perhaps other adult stem cells133.”

    From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [133]

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.

  • Q-cycle description switches ubiquinol to ubiquinone

    Minor

    The description says complex III receives ubiquinol and removes an electron from it, but then calls the same step a one-electron oxidation of ubiquinone.

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Authors
Hamanaka, R. B., & Chandel, N. S.
Affiliations
Northwestern University (US)
Corresponding author
Chandel, Navdeep S.
ORCID
Venue
Trends in Biochemical Sciences
Publisher
Elsevier BV
Published
2010-09
Volume
35
Issue
9
Pages
505-513
ISSN
0968-0004 (ISSN-L)
DOI
10.1016/j.tibs.2010.04.002
PMC
PMC2933303
OpenAlex
W2040856926
Semantic Scholar
d15e7733a704b214863986af876214605f411a00
Cited by
1,011
References
99
Citations by year
2026: 54 · 2025: 51 · 2024: 61 · 2023: 58 · 2022: 51 · 2021: 68 · 2020: 75 · 2019: 67 · 2018: 72 · 2017: 65 · 2016: 72 · 2015: 54 · 2014: 74 · 2013: 65 · 2012: 72
FWCI
5.28
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Trends in Biochemical Sciences (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (F32HL099007)
  • National Cancer Institute (R01CA123067, T32CA070085)
  • National Institute of General Medical Sciences (R01GM60472-10, R01GM060472)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
mitochondrial reactive oxygen species, signal transduction, oxidative homeostasis, NADPH oxidase, mitochondrial ROS production, cellular energy state, metabolite signaling, cellular stress signaling, stem cell maintenance, oncogenic transformation, cell survival
MeSH terms
Animals, Cell Physiological Phenomena, Humans, Mitochondria, Signal Transduction, Reactive Oxygen Species

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