Skip to main content
SpringerLink
Log in

Decline in cytochrome c oxidase activity in rat-brain mitochondria with aging. Role of peroxidized cardiolipin and beneficial effect of melatonin

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

Reactive oxygen species (ROS) are considered a key factor in mitochondrial dysfunction associated with brain aging process. Mitochondrial respiration is an important source of ROS and hence a potential contributor to brain functional changes with aging. In this study, we examined the effect of aging on cytochrome c oxidase activity and other bioenergetic processes such as oxygen consumption, membrane potential and ROS production in rat brain mitochondria. We found a significant age-dependent decline in the cytochrome c oxidase activity which was associated with parallel changes in state 3 respiration, membrane potential and with an increase in H2O2 generation. The cytochrome aa3 content was practically unchanged in mitochondria from young and aged animals. The age-dependent decline of cytochrome c oxidase activity could be restored, in situ, to the level of young animals, by exogenously added cardiolipin. In addition, exposure of brain mitochondria to peroxidized cardiolipin resulted in an inactivation of this enzyme complex. It is suggested that oxidation/depletion of cardiolipin could be responsible, at least in part, for the decline of cytochrome c oxidase and mitochondrial dysfunction in brain aging. Melatonin treatment of old animals largely prevented the age-associated alterations of mitochondrial bioenergetic parameters. These results may prove useful in elucidating the molecular mechanisms underlying mitochondrial dysfunction associated with brain aging process, and may have implications in etiopathology of age-associated neurodegenerative disorders and in the development of potential treatment strategies.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Acuña CD, Escames G, Carazo A, León J, Khaldy H, Reiter RJ (2002) Melatonin, mitochondrial homeostasis and mitochondrial-related diseases. Curr Top Med Chem 2:133–151

    Article  Google Scholar 

  • Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58:495–505

    Article  CAS  Google Scholar 

  • Berman SB, Hastings TG (1999) Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson’s disease. J Neurochem 73:1127–1137

    Article  CAS  Google Scholar 

  • Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37:911–917

    Article  CAS  Google Scholar 

  • Bondy SC, Sharma EH (2007) Melatonin and aging brain. Neurochem Int 50:571–580

    Article  CAS  Google Scholar 

  • Boveris A, Navarro A (2008) Brain mitochondrial dysfunction in aging. IUBMB Life 60:308–14

    Article  CAS  Google Scholar 

  • Castroviejo DA, López LC, Escames G, López A, García JA, Reiter RJ (2011) Melatonin-mitochondria interplay in health and disease. Curr Top Med Chem 11:221–40

    Article  CAS  Google Scholar 

  • Chakrabarti S, Munshi S, Banerjee K, Thakurta IG, Sinha M, Bagh MB (2011) Mitochondrial dysfunction during brain aging: role of oxidative stress and modulation by antioxidant supplementation. Aging Dis 2:242–56

    Google Scholar 

  • Chance B, Williams GR (1955) Respiratory enzymes in oxidative phosphorylation. J Biol Chem 217:383–394

    CAS  Google Scholar 

  • Claypool SM, Koehler CM (2012) The complexity of cardiolipin in health and disease. Trends Biochem Sci 37:32–41

    Article  CAS  Google Scholar 

  • Cocco T, Sgobbo P, Clemente M, Lopriore B, Grattagliano I, Di Paola M, Villani G (2005) Tissue-specific changes of mitochondrial functions in aged rats: effect of a long term dietary treatment with N-acetylcysteine. Free Rad Biol Med 38:796–805

    Article  CAS  Google Scholar 

  • Davey GP, Clark JB (1996) Threshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria. J Neurochem 66:1617–24

    Article  CAS  Google Scholar 

  • Davey GP, Peuchen S, Clark JB (1998) Energy thresholds in brain mitochondria. Potential involvement in neurodegeneration. J Biol Chem 273:12753–7

    Article  CAS  Google Scholar 

  • Eskola J, Laakso S (1983) Bile salt–dependent oxygenation of polyunsatured phosphatidylcholines by soybean lipoxigenase-1. Biochim Biophys Acta 75:305–311

    Google Scholar 

  • Fattoretti P, Balietti M, Giorgetti B, Grossi Y, Casoli T, Di Stefano G, Bertoni-Freddari C (2006) Testing mitochondrial metabolic competence by cytochrome oxidase preferential cytochemistry versus immunoreactivity of subunits I and IV. Rejuvenation Res 9:215–8

    Article  CAS  Google Scholar 

  • Floyd RA, Hansley K (2002) Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol Aging 23:795–807

    Article  CAS  Google Scholar 

  • Fry M, Green DE (1981) Cardiolipin requirement for electron transfer in complex I and III of the mitochondrial respiratory chain. J Biol Chem 256:1874–80

    CAS  Google Scholar 

  • Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300

    Article  CAS  Google Scholar 

  • Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20:145–7

    CAS  Google Scholar 

  • Hoch FL (1992) Cardiolipins and biomembrane function. Biochim Biophys Acta 1113:71–133

    Article  CAS  Google Scholar 

  • Jou MJ (2008) Pathophysiological and pharmacological implications of mitochondria-targeted reactive oxygen species generation in astrocytes. Adv Drug Deliv Rev 60:1512–26

    Article  CAS  Google Scholar 

  • Kagan VE, Tyurin VA, Jiang J, Tyurina YY, Ritov VB, Amoscato AA, Osipov AN, Belikova NA, Kapralov AA, Kini V, Vlasova II, Zhao Q, Zou M, Di P, Svistunenko DA, Kurnikov IV, Borisenko GG (2005) Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors. Nat Chem Biol 1:223–32

    Article  CAS  Google Scholar 

  • Kagan VE, Bayir HA, Belikova NA, Kapralov O, Tyurina YY, Tyurin VA, Jiang J, Stoyanovsky DA, Wipf P, Kochanek PM, Greenberger JS, Pitt B, Shvedova AA, Borisenko G (2009) Cytochrome c/cardiolipin relations in mitochondria: a kiss of death. Free Radic Biol Med 46:1439–53

    Article  CAS  Google Scholar 

  • Kauppinen RA, Hassinen IE (1984) Monitoring of mitochondrial membrane potential in isolated perfused rat heart. Am J Physiol 247:H508–H516

    CAS  Google Scholar 

  • Kiebish MA, Han X, Cheng H, Chuang JH, Seyfried TN (2008) Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer. J Lipid Res 49:2545–56

    Article  CAS  Google Scholar 

  • Kish SJ, Bergeron C, Rajput A, Dozic S, Mastrogiacomo F, Chang LJ, Wilson JM, Di Stefano LM, Nobrega JN (1992) Brain cytochrome oxidase in Alzheimer’s disease. J Neurochem 59:776–9

    Article  CAS  Google Scholar 

  • Korshunov SS, Krasnikov BF, Pereverzev MO, Skulachev VP (1999) The antioxidant functions of cytochrome c. FEBS Lett 462:192–8

    Article  CAS  Google Scholar 

  • Kuboyama M, Yong FC, King TE (1972) Studies on cytochrome oxidase. Preparation and some properties of cardiac cytochrome oxidase. J Biol Chem 247:6375–83

    CAS  Google Scholar 

  • Letellier T, Heinrich R, Malgat M, Mazat JP (1994) The kinetic basis of threshold effects observed in mitochondrial diseases: a systemic approach. Biochem J 302:171–4

    CAS  Google Scholar 

  • Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–95

    Article  CAS  Google Scholar 

  • Loschen G, Flohè L, Chance B (1971) Respiratory chain linked H2O2 production in pigeon heart mitochondria. FEBS Lett 18:261–264

    Article  CAS  Google Scholar 

  • Losito I, Conte E, Introna B, Megli FM, Palmisano F (2011) Improved specificity of cardiolipin peroxidation by soybean lipoxygenase: a liquid chromatography -electrospray ionization mass spectrometry investigation. J Mass Spectrom 46:1255–62

    Article  CAS  Google Scholar 

  • Miquel J, Fleming J (1986) Theoretical and experimental support for an “oxygen radical injury” hypothesis of cell aging. In: Johnson JE, Waldorf R, Harman D, Miquel J (eds) Free radicals, aging and degenerative diseases. Alan R.Liss, New York, pp 51–74

    Google Scholar 

  • Musatov A (2006) Contribution of peroxidized cardiolipin to inactivation of bovine heart cytochrome c oxidase. Free Radic Biol Med 41:238–46

    Article  CAS  Google Scholar 

  • Mutisya EM, Bowling AC, Beal MF (1994) Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem 63:2179–84

    Article  CAS  Google Scholar 

  • Navarro A, Boveris A (2007) The mitochondrial energy transduction and the aging process. Am J Physiol Cell Physiol 292:C670–C686

    Article  CAS  Google Scholar 

  • Ott M, Gogvadze V, Orrenius S, Zhivotovsky B (2007) Mitochondria, oxidative stress and cell death. Apoptosis 12:913–22

    Article  CAS  Google Scholar 

  • Pamplona R (2008) Membrane phospholipids, lipoxidative damage and molecular integrity: a causal role in aging and longevity. Biochim Biophys Acta 1777:1249–62

    Article  CAS  Google Scholar 

  • Paradies G, Ruggiero FM, Petrosillo G, Quagliariello E (1997) Age-dependent decline in the cytochrome c oxidase activity in rat heart mitochondria: role of cardiolipin. FEBS Lett 406:136–8

    Article  CAS  Google Scholar 

  • Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Serena D, Ruggiero FM (1999) Lipid peroxidation and alterations to oxidative metabolism in mitochondria isolated from rat heart subjected to ischemia and reperfusion. Free Radic Biol Med 27:42–50

    Article  CAS  Google Scholar 

  • Paradies G, Petrosillo G, Pistolese M, Ruggiero FM (2000) The effect of reactive oxygen species generated from the mitochondrial electron transport chain on the cytochrome c oxidase activity and on the cardiolipin content in bovine heart submitochondrial particles. FEBS Lett 466:323–6

    Article  CAS  Google Scholar 

  • Paradies G, Petrosillo G, Paradies V, Ruggiero FM (2009) Role of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease. Cell Calcium 45:643–50

    Article  CAS  Google Scholar 

  • Paradies G, Petrosillo G, Paradies V, Reiter RJ, Ruggiero FM (2010a) Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease. J Pineal Res 48:297–310

    Article  CAS  Google Scholar 

  • Paradies G, Petrosillo G, Paradies V, Ruggiero FM (2010b) Oxidative stress, mitochondrial bioenergetics, and cardiolipin in aging. Free Radic Biol Med 48:1286–95

    Article  CAS  Google Scholar 

  • Paradies G, Petrosillo G, Paradies V, Ruggiero FM (2011) Mitochondrial dysfunction in brain aging: role of oxidative stress and cardiolipin. Neurochem Int 58:447–57

    Article  CAS  Google Scholar 

  • Peng TI, Hsiao CW, Reiter RJ, Tanaka M, Lai YK, Jou MJ (2012) mtDNA T8993G mutation-induced mitochondrial complex V inhibition augments cardiolipin-dependent alterations in mitochondrial dynamics during oxidative, Ca(2+), and lipid insults in NARP cybrids: a potential therapeutic target for melatonin. J Pineal Res 52:93–106

    Article  CAS  Google Scholar 

  • Petrosillo G, Di Venosa N, Pistolese M, Casanova G, Tiravanti E, Colantuono G, Federici A, Paradies G, Ruggiero FM (2006) Protective effect of melatonin against mitochondrial dysfunction associated with cardiac ischemia- reperfusion: role of cardiolipin. FASEB J 20:269–76

    Article  CAS  Google Scholar 

  • Petrosillo G, Fattoretti P, Matera M, Ruggiero FM, Bertoni-Freddari C, Paradies G (2008a) Melatonin prevents age-related mitochondrial dysfunction in rat brain via cardiolipin protection. Rejuvenation Res 11:935–43

    Article  CAS  Google Scholar 

  • Petrosillo G, Matera M, Casanova G, Ruggiero FM, Paradies G (2008b) Mitochondrial dysfunction in rat brain with aging involvement of complex I, reactive oxygen species and cardiolipin. Neurochem Int 53:126–31

    Article  CAS  Google Scholar 

  • Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, Fiore T, Paradies G (2009a) Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol 297:H1487–9

    Article  CAS  Google Scholar 

  • Petrosillo G, Moro N, Ruggiero FM, Paradies G (2009b) Melatonin inhibits cardiolipin peroxidation in mitochondria and prevents the mitochondrial permeability transition and cytochrome c release. Free Radic Biol Med 47:969–74

    Article  CAS  Google Scholar 

  • Robinson NC (1993) Functional binding of cardiolipin to cytochrome c oxidase. J Bioenerg Biomembr 25:153–63

    Article  CAS  Google Scholar 

  • Sandhu SK, Kaur G (2003) Mitochondrial electron transport chain complexes in aging rat brain and lymphocytes. Biogerontology 4:19–29

    Article  CAS  Google Scholar 

  • Schlame M, Ren M (2009) The role of cardiolipin in the structural organization of mitochondrial membranes. Biochim Biophys Acta 1788:2080–3

    Article  CAS  Google Scholar 

  • Schlame M, Rua D, Greenberg ML (2000) The biosynthesis and functional role of cardiolipin. Prog Lipid Res 39:257–88

    Article  CAS  Google Scholar 

  • Schug ZT, Gottlieb E (2009) Cardiolipin acts as a mitochondrial signalling platform to launch apoptosis. Biochim Biophys Acta 1788:2022–31

    Article  CAS  Google Scholar 

  • Sedlák E, Robinson NC (1999) Phospholipase A(2) digestion of cardiolipin bound to bovine cytochrome c oxidase alters both activity and quaternary structure. Biochemistry 38:14966–72

    Article  Google Scholar 

  • Sen T, Sen N, Jana S, Khan FH, Chatterjee U, Chakrabarti S (2007) Depolarization and cardiolipin depletion in aged rat brain mitochondria: relationship with oxidative stress and electron transport chain activity. Neurochem Int 50:719–25

    Article  CAS  Google Scholar 

  • Shigenaga MK, Hagen TM, Ames BN (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 91:10771–8

    Article  CAS  Google Scholar 

  • Skulachev MV, Antonenko YN, Anisimov VN, Chernyak BV, Cherepanov DA, Chistyakov VA, Egorov MV, Kolosova NG, Korshunova GA, Lyamzaev KG, Plotnikov EY, Roginsky VA, Savchenko AY, Severina II, Severin FF, Shkurat TP, Tashlitsky VN, Shidlovsky KM, Vyssokikh MY, Zamyatnin AA Jr, Zorov DB, Skulachev VP (2011) Mitochondrial-targeted plastoquinone derivatives. Effect on senescence and acute age-related pathologies. Curr Drug Targets 12:800–26

    Article  CAS  Google Scholar 

  • Smith L, Camerino PW (1963) Comparison of polarographic and spectrophotometric assays for cytochrome oxidase activity. Biochemistry 2:1428–1432

    Article  CAS  Google Scholar 

  • Srere PA (1969) Methods Enzymol 13:3–11

    Article  CAS  Google Scholar 

  • Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ (2007) One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 42:28–42

    Article  CAS  Google Scholar 

  • Toescu EC, Myronova N, Verkhratsky A (2000) Age-related structural and functional changes of brain mitochondria. Cell Calcium 28:329–338

    Article  CAS  Google Scholar 

  • Villani G, Attardi G (2000) In vivo control of respiration by cytochrome c oxidase in human cells. Free Radic Biol Med 29:202–10

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Biomembranes and Bioenergetics, National Research Council of Italy, Bari, Italy

    Giuseppe Petrosillo

  2. Department Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via E Orabona, 4, Bari, Italy

    Valentina De Benedictis, Francesca M. Ruggiero & Giuseppe Paradies

Authors
  1. Giuseppe Petrosillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valentina De Benedictis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesca M. Ruggiero
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giuseppe Paradies
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giuseppe Paradies.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Petrosillo, G., De Benedictis, V., Ruggiero, F.M. et al. Decline in cytochrome c oxidase activity in rat-brain mitochondria with aging. Role of peroxidized cardiolipin and beneficial effect of melatonin. J Bioenerg Biomembr 45, 431–440 (2013). https://doi.org/10.1007/s10863-013-9505-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-013-9505-0

Keywords

Search

Navigation