Skip to main content
SpringerLink
Log in

Mitochondrial and Free Radical Metabolism – Biological and Pathological Implications

  • Reference work entry
  • First Online:
Book cover Systems Biology of Free Radicals and Antioxidants

  • 429 Accesses

Abstract

Oxidative stress is believed to contribute to the pathogenesis of many diseases including metabolic and cardiovascular diseases, cancers, and the normal process of aging. In cells, mitochondria are the primary source of reactive oxygen species (ROS) and have been considered exclusively as unwanted by-products of oxidative phosphorylation. There is now growing evidences that redox signaling can occur by mitochondrial generation of free radicals. Injurious effects of excessive ROS production in cells are well documented. These oxidants may have deleterious effects by oxidizing proteins, lipids, and DNA, leading, for example, to the initiation of apoptosis. In this review, we will focus on the apparent dual role of mitochondrial ROS production, “good” biological or “bad” pathological. These findings suggest that therapeutic intervention aimed at decreasing ROS formation in various diseases needs to be reconsidered.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 1,999.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 2,999.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

8 oxodG:

8-Oxo-2′-deoxyguanosine

CoQ:

Coenzyme Q

E3:

Dihydrolipoamide dehydrogenase

eNOS:

Endothelial nitric oxide synthase

ETC:

Electron transport chain

ETF:

Electron transfer protein flavoprotein

GSH:

Glutathione system

H2O2 :

Hydrogen peroxide

HIF:

Hypoxia-inducing factor

MCL-1:

Myeloid cell leukemia-1

MFRTA:

Mitochondrial free radical theory of aging

MnSOD:

Manganese superoxide dismutase

NFκB:

Nuclear factor-kappa B

NO:

Nitric oxide

O2 :

Oxygen

O2 •− :

Superoxide anion

PKC:

Protein kinase C

PTEN:

Lipid phosphatase and tumor suppressor

QH− :

Semiubiquinone

QH2:

Ubiquinol

ROS:

Reactive oxygen species

TNFα:

Tumor necrosis factor alpha

TRXSH2:

Thioredoxin systems

UCP:

Uncoupling proteins

VEGF:

Vascular endothelial growth factor

References

  • Brand MD (2010) The sites and topology of mitochondrial superoxide production. Exp Gerontol 45:466–472

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    Article  CAS  PubMed  Google Scholar 

  • Cakir Y, Yang Z, Knight CA, Pompilius M, Westbrook D, Bailey SM, Pinkerton KE, Ballinger SW (2007) Effect of alcohol and tobacco smoke on mtDNA damage and atherogenesis. Free Radic Biol Med 43:1279–1288

    Article  CAS  PubMed  Google Scholar 

  • Cape JL, Bowman MK, Kramer DM (2007) A semiquinone intermediate generated at the Qo site of the cytochrome bc1 complex: importance for the Q-cycle and superoxide production. Proc Natl Acad Sci USA 104:7887–7892

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chakravarti B, Chakravarti DN (2007) Oxidative modification of proteins: age-related changes. Gerontology 53:128–139

    Article  CAS  PubMed  Google Scholar 

  • Chen Q, Moghaddas S, Hoppel CL, Lesnefsky EJ (2008) Ischemic defects in the electron transport chain increase the production of reactive oxygen species from isolated rat heart mitochondria. Am J Physiol Cell Physiol 294:C460–C466

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Azad MB, Gibson SB (2009) Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ 16:1040–1052

    Article  CAS  PubMed  Google Scholar 

  • Di Lisa F, Kaludercic N, Carpi A, Menabo R, Giorgio M (2009) Mitochondrial pathways for ROS formation and myocardial injury: the relevance of p66Shc and monoamine oxidase. Basic Res Cardiol 104:131–139

    Article  PubMed  Google Scholar 

  • Dikalova AE, Bikineyeva AT, Budzyn K, Nazarewicz RR, McCann L, Lewis W, Harrison DG, Dikalov SI (2010) Therapeutic targeting of mitochondrial superoxide in hypertension. Circ Res 107:106–116

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Doonan R, McElwee JJ, Matthijssens F, Walker GA, Houthoofd K, Back P, Matscheski A, Vanfleteren JR, Gems D (2008) Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev 22:3236–3241

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fridell YW, Sánchez-Blanco A, Silvia BA, Helfand SL (2005) Targeted expression of the human uncoupling protein 2 (hUCP2) to adult neurons extends life span in the fly. Cell Metab 1:145–152

    Article  CAS  PubMed  Google Scholar 

  • Gao P, Zhang H, Dinavahi R, Li F, Xiang Y, Raman V, Bhujwalla ZM, Felsher DW, Cheng L, Pevsner J, Lee LA, Semenza GL, Dang CV (2007) HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12:230–238

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gao W, Xu K, Li P, Tang B (2011) Functional roles of superoxide and hydrogen peroxide generated by mitochondrial DNA mutation in regulating tumorigenicity of HepG2 cells. Cell Biochem Funct 29:400–407

    Article  CAS  PubMed  Google Scholar 

  • Goh J, Enns L, Fatemie S, Hopkins H, Morton J, Pettan-Brewer C, Ladiges W (2011) Mitochondrial targeted catalase suppresses invasive breast cancer in mice. BMC Cancer 11:191

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gopalakrishna R, Jaken S (2000) Protein kinase C signaling and oxidative stress. Free Radic Biol Med 28:1349–1361

    Article  CAS  PubMed  Google Scholar 

  • Gosselin K, Martien S, Pourtier A, Vercamer C, Ostoich P, Morat L, Sabatier L, Duprez L, T’kint de Roodenbeke C, Gilson E, Malaquin N, Wernert N, Slijepcevic P, Ashtari M, Chelli F, Deruy E, Vandenbunder B, De Launoit Y, Abbadie C (2009) Senescence-associated oxidative DNA damage promotes the generation of neoplastic cells. Cancer Res 69:7917–7925

    Article  CAS  PubMed  Google Scholar 

  • Harman D (1992) Free radical theory of aging. Mutat Res 275:257–266

    Article  CAS  PubMed  Google Scholar 

  • Hekimi S, Lapointe J, Wen Y (2011) Taking a “good” look at free radicals in the aging process. Trends Cell Biol 21:569–576

    Article  CAS  PubMed  Google Scholar 

  • Hirst J, King MS, Pryde KR (2008) The production of reactive oxygen species by complex I. Biochem Soc Trans 36:976–980

    Article  CAS  PubMed  Google Scholar 

  • Howes RM (2006) The free radical fantasy: a panoply of paradoxes. Ann N Y Acad Sci 1067:22–26

    Article  CAS  PubMed  Google Scholar 

  • Hwang AB, Lee SJ (2011) Regulation of life span by mitochondrial respiration: the HIF-1 and ROS connection. Aging (Albany NY) 3:304–310

    CAS  Google Scholar 

  • Imoto K, Kukidome D, Nishikawa T, Matsuhisa T, Sonoda K, Fujisawa K, Yano M, Motoshima H, Taguchi T, Tsuruzoe K, Matsumura T, Ichijo H, Araki E (2006) Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling. Diabetes 55:1197–1204

    Article  CAS  PubMed  Google Scholar 

  • Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, Nakada K, Honma Y, Hayashi J (2008) ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320:661–664

    Article  CAS  PubMed  Google Scholar 

  • Jang YC, Pérez VI, Song W, Lustgarten MS, Salmon AB, Mele J, Qi W, Liu Y, Liang H, Chaudhuri A, Ikeno Y, Epstein CJ, Van Remmen H, Richardson A (2009) Overexpression of Mn superoxide dismutase does not increase life span in mice. J Gerontol A Biol Sci Med Sci 64:1114–1125

    Article  PubMed  Google Scholar 

  • Kim EH, Sohn S, Kwon HJ, Kim SU, Kim MJ, Lee SJ, Choi KS (2007) Sodium selenite induces superoxide-mediated mitochondrial damage and subsequent autophagic cell death in malignant glioma cells. Cancer Res 67:6314–6324

    Article  CAS  PubMed  Google Scholar 

  • Klimova T, Chandel NS (2008) Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ 15:660–666

    Article  CAS  PubMed  Google Scholar 

  • Koopman WJ, Nijtmans LG, Dieteren CE, Roestenberg P, Valsecchi F, Smeitink JA, Willems PH (2010) Mammalian mitochondrial complex I: biogenesis, regulation, and reactive oxygen species generation. Antioxid Redox Signal 12:1431–1470

    Article  CAS  PubMed  Google Scholar 

  • Kushnareva Y, Murphy AN, Andreyev A (2002) Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation-reduction state. Biochem J 368:545–553

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kussmaul L, Hirst J (2006) The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc Natl Acad Sci USA 103:7607–7612

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kwon J, Lee SR, Yang KS, Ahn Y, Kim YJ, Stadtman ER, Rhee SG (2004) Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. Proc Natl Acad Sci USA 101:16419–16424

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Leduc L, Levy E, Bouity-Voubou M, Delvin E (2010) Fetal programming of atherosclerosis: possible role of the mitochondria. Eur J Obstet Gynecol Reprod Biol 149:127–130

    Article  CAS  PubMed  Google Scholar 

  • Leloup C, Tourrel-Cuzin C, Magnan C, Karaca M, Castel J, Carneiro L, Colombani AL, Ktorza A, Casteilla L, Pénicaud L (2009) Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion. Diabetes 58:673–681

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ma Q, Cavallin LE, Yan B, Zhu S, Duran EM, Wang H, Hale LP, Dong C, Cesarman E, Mesri EA, Goldschmidt-Clermont PJ (2009) Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi’s sarcoma. Proc Natl Acad Sci USA 106:8683–8688

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Madamanchi NR, Runge MS (2007) Mitochondrial dysfunction in atherosclerosis. Circ Res 100:460–473

    Article  CAS  PubMed  Google Scholar 

  • Marshall HE, Merchant K, Stamler JS (2000) Nitrosation and oxidation in the regulation of gene expression. FASEB J 14:1889–1900

    Article  CAS  PubMed  Google Scholar 

  • Mecocci P, MacGarvey U, Kaufman AE, Koontz D, Shoffner JM, Wallace DC, Beal MF (1993) Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann Neurol 34:609–616

    Article  CAS  PubMed  Google Scholar 

  • Modica-Napolitano JS, Singh KK (2002) Mitochondria as targets for detection and treatment of cancer. Expert Rev Mol Med 4:1–19

    Article  PubMed  Google Scholar 

  • Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nieto-Vazquez I, Fernández-Veledo S, Krämer DK, Vila-Bedmar R, Garcia-Guerra L, Lorenzo M (2008) Insulin resistance associated to obesity: the link TNF-alpha. Arch Physiol Biochem 114:183–194

    Article  CAS  PubMed  Google Scholar 

  • Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790

    Article  CAS  PubMed  Google Scholar 

  • Osyczka A, Moser CC, Dutton PL (2005) Fixing the Q cycle. Trends Biochem Sci 30:176–182

    Article  CAS  PubMed  Google Scholar 

  • Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Federici A, Ruggiero FM (2004) Decrease in mitochondrial complex I activity in ischemic/reperfused rat heart: involvement of reactive oxygen species and cardiolipin. Circ Res 94:53–59

    Article  CAS  PubMed  Google Scholar 

  • Perrone GG, Tan SX, Dawes IW (2008) Reactive oxygen species and yeast apoptosis. Biochim Biophys Acta 1783:1354–1368

    Article  CAS  PubMed  Google Scholar 

  • Perry JJ, Shin DS, Getzoff ED, Tainer JA (2010) The structural biochemistry of the superoxide dismutases. Biochim Biophys Acta 1804:245–262

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Petrosillo G, Ruggiero FM, Paradies G (2003) Role of reactive oxygen species and cardiolipin in the release of cytochrome c from mitochondria. FASEB J 17:2202–2208

    Article  CAS  PubMed  Google Scholar 

  • Petrosillo G, Matera M, Moro N, Ruggiero FM, Paradies G (2009) Mitochondrial complex I dysfunction in rat heart with aging: critical role of reactive oxygen species and cardiolipin. Free Radic Biol Med 46:88–94

    Article  CAS  PubMed  Google Scholar 

  • Qiao S, Murakami K, Zhao Q, Wang B, Seo H, Yamashita H, Li X, Iwamoto T, Ichihara M, Yoshino M (2012) Mimosine-induced apoptosis in c6 glioma cells requires the release of mitochondria-derived reactive oxygen species and p38, JNK Activation. Neurochem Res 37:417–427

    Article  CAS  PubMed  Google Scholar 

  • Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, Werb Z, Bissell MJ (2005) Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436:123–127

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rhee SG, Yang KS, Kang SW, Woo HA, Chang TS (2005) Controlled elimination of intracellular H(2)O(2): regulation of peroxiredoxin, catalase, and glutathione peroxidase via post-translational modification. Antioxid Redox Signal 7:619–626

    Article  CAS  PubMed  Google Scholar 

  • Rigoulet M, Yoboue ED, Devin A (2011) Mitochondrial ROS generation and its regulation: mechanisms involved in H(2)O(2) signaling. Antioxid Redox Signal 14:459–468

    Article  CAS  PubMed  Google Scholar 

  • Ristow M, Schmeisser S (2011) Extending life span by increasing oxidative stress. Free Radic Biol Med 51:327–336

    Article  CAS  PubMed  Google Scholar 

  • Sakai K, Matsumoto K, Nishikawa T, Suefuji M, Nakamaru K, Hirashima Y, Kawashima J, Shirotani T, Ichinose K, Brownlee M, Araki E (2003) Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic beta-cells. Biochem Biophys Res Commun 300:216–222

    Article  CAS  PubMed  Google Scholar 

  • Scherz-Shouval R, Elazar Z (2011) Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 36:30–38

    Article  CAS  PubMed  Google Scholar 

  • Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z (2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26:1749–1760

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308:1909–1911

    Article  CAS  PubMed  Google Scholar 

  • Someya S, Prolla TA (2010) Mitochondrial oxidative damage and apoptosis in age-related hearing loss. Mech Ageing Dev 131:480–486

    Article  CAS  PubMed  Google Scholar 

  • Starkov AA, Fiskum G, Chinopoulos C, Lorenzo BJ, Browne SE, Patel MS, Beal MF (2004) Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci 24:7779–7788

    Article  CAS  PubMed  Google Scholar 

  • Sun J, Molitor J, Tower J (2004) Effects of simultaneous over-expression of Cu/ZnSOD and MnSOD on Drosophila melanogaster life span. Mech Ageing Dev 125:341–349

    Article  CAS  PubMed  Google Scholar 

  • Tahara EB, Navarete FD, Kowaltowski AJ (2009) Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation. Free Radic Biol Med 46:1283–1297

    Article  CAS  PubMed  Google Scholar 

  • Thomas SR, Witting PK, Drummond GR (2008) Redox control of endothelial function and dysfunction: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal 10:1713–1765

    Article  CAS  PubMed  Google Scholar 

  • Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang TT, Nelson J, Strong R, Richardson A (2003) Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics 16:29–37

    Article  PubMed  Google Scholar 

  • Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GR, Chandel NS (2010) Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA 107:8788–8793

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yang W, Hekimi S (2010) A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS Biol 8:e1000556

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oxidative Stress and Metabolic Diseases, INSERM U1063, Angers University, Angers, France

    Lucie Duluc, Ramaroson Andriantsitohaina & Gilles Simard

  2. INSERM U1063, Institut de Biologie en Santé – IBS – IRIS, Rue des Capucins, 49045, Angers, France

    Ramaroson Andriantsitohaina

Authors
  1. Lucie Duluc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ramaroson Andriantsitohaina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gilles Simard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ramaroson Andriantsitohaina .

Editor information

Editors and Affiliations

  1. Department of Pharmacology and Therapeutics, University of British Colombia, Vancouver, British Columbia, Canada

    Ismail Laher

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Berlin Heidelberg

About this entry

Cite this entry

Duluc, L., Andriantsitohaina, R., Simard, G. (2014). Mitochondrial and Free Radical Metabolism – Biological and Pathological Implications. In: Laher, I. (eds) Systems Biology of Free Radicals and Antioxidants. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-30018-9_7

Download citation

Publish with us

Policies and ethics

Search

Navigation