Skip to main content
SpringerLink
Log in

Endotoxemia impairs heart mitochondrial function by decreasing electron transfer, ATP synthesis and ATP content without affecting membrane potential

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

Abstract

Acute endotoxemia (LPS, 10 mg/kg ip, Sprague Dawley rats, 45 days old, 180 g) decreased the O2 consumption of rat heart (1 mm3 tissue cubes) by 33% (from 4.69 to 3.11 μmol O2/min. g tissue). Mitochondrial O2 consumption and complex I activity were also decreased by 27% and 29%, respectively. Impaired respiration was associated to decreased ATP synthesis (from 417 to 168 nmol/min. mg protein) and ATP content (from 5.40 to 4.18 nmol ATP/mg protein), without affecting mitochondrial membrane potential. This scenario is accompanied by an increased production of O ●−2 and H2O2 due to complex I inhibition. The increased NO production, as shown by 38% increased mtNOS biochemical activity and 31% increased mtNOS functional activity, is expected to fuel an increased ONOO− generation that is considered relevant in terms of the biochemical mechanism. Heart mitochondrial bioenergetic dysfunction with decreased O2 uptake, ATP production and contents may indicate that preservation of mitochondrial function will prevent heart failure in endotoxemia.

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

  • Alvarez S, Boveris A (2004) Mitochondrial nitric oxide metabolism in rat muscle during endotoxemia. Free Radic Biol Med 37(9):1472–1478

    Article  CAS  Google Scholar 

  • Antunes F, Boveris A, Cadenas E (2007) On the biologic role of the reaction of NO with oxidized cytochrome c oxidase. Antioxid Redox Signal 9(10):1569–1579

    Article  CAS  Google Scholar 

  • Azzi A, Montecucco C, Richter C (1975) The use of acetylated ferricytochrome c for the detection of superoxide radicals produced in biological membranes. Biochem Biophys Res Commun 65(2):597–603

    Article  CAS  Google Scholar 

  • Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A 87(4):1620–1624

    Article  CAS  Google Scholar 

  • Beckman JS, Carson M, Smith CD, Koppenol WH (1993) ALS, SOD and peroxynitrite. Nature 364(6438):584

    Article  CAS  Google Scholar 

  • Bornhovd C, Vogel F, Neupert W, Reichert AS (2006) Mitochondrial membrane potential is dependent on the oligomeric state of F1F0-ATP synthase supracomplexes. J Biol Chem 281(20):13990–13998

    Article  Google Scholar 

  • Boveris A (1984) Determination of the production of superoxide radicals and hydrogen peroxide in mitochondria. Methods Enzymol 105:429–435

    Article  CAS  Google Scholar 

  • Boveris A, Cadenas E (1975) Mitochondrial production of superoxide anions and its relationship to the antimycin insensitive respiration. FEBS Lett 54(3):311–314

    Article  CAS  Google Scholar 

  • Boveris A, Costa LE, Cadenas E, Poderoso JJ (1999) Regulation of mitochondrial respiration by adenosine diphosphate, oxygen, and nitric oxide synthase. Methods Enzymol 301:188–198

    Article  CAS  Google Scholar 

  • Boveris A, Alvarez S, Navarro A (2002a) The role of mitochondrial nitric oxide synthase in inflammation and septic shock. Free Radic Biol Med 33(9):1186–1193

    Article  CAS  Google Scholar 

  • Boveris A, Arnaiz SL, Bustamante J, Alvarez S, Valdez L, Boveris AD et al (2002b) Pharmacological regulation of mitochondrial nitric oxide synthase. Methods Enzymol 359:328–339

    Article  CAS  Google Scholar 

  • Boveris A, Valdez LB, Alvarez S, Zaobornyj T, Boveris AD, Navarro A (2003) Kidney mitochondrial nitric oxide synthase. Antioxid Redox Signal 5(3):265–271

    Article  CAS  Google Scholar 

  • Brandes RP, Koddenberg G, Gwinner W, Kim D, Kruse HJ, Busse R et al (1999) Role of increased production of superoxide anions by NAD(P)H oxidase and xanthine oxidase in prolonged endotoxemia. Hypertension 33(5):1243–1249

    CAS  Google Scholar 

  • Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R et al (2002) Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360(9328):219–223

    Article  CAS  Google Scholar 

  • Cadenas E, Boveris A (1980) Enhancement of hydrogen peroxide formation by protophores and ionophores in antimycin-supplemented mitochondria. Biochem J 188(1):31–37

    CAS  Google Scholar 

  • Callahan LA, Supinski GS (2005) Downregulation of diaphragm electron transport chain and glycolytic enzyme gene expression in sepsis. J Appl Physiol 99(3):1120–1126

    Article  Google Scholar 

  • Carre JE, Orban JC, Re L, Felsmann K, Iffert W, Bauer M et al (2010) Survival in critical illness is associated with early activation of mitochondrial biogenesis. Am J Respir Crit Care Med 182(6):745–751

    Article  Google Scholar 

  • Chance B, Sies H, Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59(3):527–605

    CAS  Google Scholar 

  • Cleeter MW, Cooper JM, Schapira AH (2001) Nitric oxide enhances MPP(+) inhibition of complex I. FEBS Lett 504(1–2):50–52

    Article  CAS  Google Scholar 

  • Crouser ED, Julian MW, Huff JE, Joshi MS, Bauer JA, Gadd ME et al (2004) Abnormal permeability of inner and outer mitochondrial membranes contributes independently to mitochondrial dysfunction in the liver during acute endotoxemia. Crit Care Med 32(2):478–488

    Article  CAS  Google Scholar 

  • Dionisi O, Galeotti T, Terranova T, Azzi A (1975) Superoxide radicals and hydrogen peroxide formation in mitochondria from normal and neoplastic tissues. Biochim Biophys Acta 403(2):292–300

    CAS  Google Scholar 

  • Emaus RK, Grunwald R, Lemasters JJ (1986) Rhodamine 123 as a probe of transmembrane potential in isolated rat-liver mitochondria: spectral and metabolic properties. Biochim Biophys Acta 850(3):436–448

    Article  CAS  Google Scholar 

  • Escames G, Lopez LC, Ortiz F, Lopez A, Garcia JA, Ros E et al (2007) Attenuation of cardiac mitochondrial dysfunction by melatonin in septic mice. FEBS J 274(8):2135–2147

    Article  CAS  Google Scholar 

  • Fink MP (2002) Bench-to-bedside review: cytopathic hypoxia. Crit Care 6(6):491–499

    Article  Google Scholar 

  • Franco MC, Arciuch VG, Peralta JG, Galli S, Levisman D, Lopez LM et al (2006) Hypothyroid phenotype is contributed by mitochondrial complex I inactivation due to translocated neuronal nitric-oxide synthase. J Biol Chem 281(8):4779–4786

    Article  CAS  Google Scholar 

  • Galkin A, Abramov AY, Frakich N, Duchen MR, Moncada S (2009) Lack of oxygen deactivates mitochondrial complex I: implications for ischemic injury? J Biol Chem 284(52):36055–36061

    Article  CAS  Google Scholar 

  • Ganster RW, Geller DA (2000) Molecular regulation of inducible nitric oxide synthase. In: Ignarro L (ed) Nitric oxide: biology and pathobiology (pp. 129–156). Academic Press

    Google Scholar 

  • Lam PY, Yin F, Hamilton RT, Boveris A, Cadenas E (2009) Elevated neuronal nitric oxide synthase expression during ageing and mitochondrial energy production. Free Radic Res 43(5):431–439

    Article  CAS  Google Scholar 

  • Li Y, Zhu H, Kuppusamy P, Roubaud V, Zweier JL, Trush MA (1998) Validation of lucigenin (bis-N-methylacridinium) as a chemilumigenic probe for detecting superoxide anion radical production by enzymatic and cellular systems. J Biol Chem 273(4):2015–2023

    Article  CAS  Google Scholar 

  • Lores-Arnaiz S, D’Amico G, Czerniczyniec A, Bustamante J, Boveris A (2004) Brain mitochondrial nitric oxide synthase: in vitro and in vivo inhibition by chlorpromazine. Arch Biochem Biophys 430(2):170–177

    Article  CAS  Google Scholar 

  • Maack C, O’Rourke B (2007) Excitation-contraction coupling and mitochondrial energetics. Basic Res Cardiol 102(5):369–392

    Article  CAS  Google Scholar 

  • Navarro A, Boveris A, Bandez MJ, Sanchez-Pino MJ, Gomez C, Muntane G et al (2009) Human brain cortex: mitochondrial oxidative damage and adaptive response in Parkinson disease and in dementia with Lewy bodies. Free Radic Biol Med 46(12):1574–1580

    Article  CAS  Google Scholar 

  • Navarro A, Bandez MJ, Gomez C, Repetto MG, Boveris A (2010) Effects of rotenone and pyridaben on complex I electron transfer and on mitochondrial nitric oxide synthase functional activity. J Bioenerg Biomembr 42(5):405–412

    Article  CAS  Google Scholar 

  • Parihar MS, Parihar A, Villamena FA, Vaccaro PS, Ghafourifar P (2008) Inactivation of mitochondrial respiratory chain complex I leads mitochondrial nitric oxide synthase to become pro-oxidative. Biochem Biophys Res Commun 367(4):761–767

    Article  CAS  Google Scholar 

  • Poderoso JJ, Fernandez S, Carreras MC, Tchercanski D, Acevedo C, Rubio M et al (1994) Liver oxygen uptake dependence and mitochondrial function in septic rats. Circ Shock 44(4):175–182

    CAS  Google Scholar 

  • Poderoso JJ, Carreras MC, Lisdero C, Riobo N, Schopfer F, Boveris A (1996) Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles. Arch Biochem Biophys 328(1):85–92

    Article  CAS  Google Scholar 

  • Protti A, Singer M (2007) Strategies to modulate cellular energetic metabolism during sepsis. In: Novartis Foundation (ed) Sepsis: new insights, new therapies (pp. 7–20) Wiley & sons, Ltd.

    Article  CAS  Google Scholar 

  • Reynolds CM, Suliman HB, Hollingsworth JW, Welty-Wolf KE, Carraway MS, Piantadosi CA (2009) Nitric oxide synthase-2 induction optimizes cardiac mitochondrial biogenesis after endotoxemia. Free Radic Biol Med 46(5):564–572

    Article  CAS  Google Scholar 

  • Scaduto RC Jr, Grotyohann LW (1999) Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys J 76(1 Pt 1):469–477

    Article  CAS  Google Scholar 

  • Schafer E, Seelert H, Reifschneider NH, Krause F, Dencher NA, Vonck J (2006) Architecture of active mammalian respiratory chain supercomplexes. J Biol Chem 281(22):15370–15375

    Article  Google Scholar 

  • Stadler K, Bonini MG, Dallas S, Jiang J, Radi R, Mason RP et al (2008) Involvement of inducible nitric oxide synthase in hydroxyl radical-mediated lipid peroxidation in streptozotocin-induced diabetes. Free Radic Biol Med 45(6):866–874

    Article  CAS  Google Scholar 

  • Svistunenko DA, Davies N, Brealey D, Singer M, Cooper CE (2006) Mitochondrial dysfunction in patients with severe sepsis: an EPR interrogation of individual respiratory chain components. Biochim Biophys Acta 1757(4):262–272

    Article  CAS  Google Scholar 

  • Szabó C (2000) Pathophysiological roles of nitric oxide in inflammation (Nitric Oxide: Biology and Pathobiology). Academic, San Diego

    Google Scholar 

  • Valdez LB, Zaobornyj T, Boveris A (2005) Functional activity of mitochondrial nitric oxide synthase. Methods Enzymol 396:444–455

    Article  CAS  Google Scholar 

  • Valdez LB, Zaobornyj T, Boveris A (2006) Mitochondrial metabolic states and membrane potential modulate mtNOS activity. Biochim Biophys Acta 1757(3):166–172

    Article  CAS  Google Scholar 

  • Vanasco V, Cimolai MC, Evelson P, Alvarez S (2008) The oxidative stress and the mitochondrial dysfunction caused by endotoxemia are prevented by alpha-lipoic acid. Free Radic Res 42(9):815–823

    Article  CAS  Google Scholar 

  • Ventura-Clapier R, Garnier A, Veksler V, Joubert F (2011) Bioenergetics of the failing heart. Biochim Biophys Acta 1813(7):1360–1372

    Article  CAS  Google Scholar 

  • Villani G & Attardi G (2007) Polarographic assay of respiratory chain complex activity. In: Pon LA & Schon EA (eds) Methods in cell biology: mitochondria (2nd ed., Vol. 80, pp. 121–134). Elsevier

  • Vivez-Bauza C, Yang L & Manfredi G (2007) Assay of mitochondrial ATP synthesis in animal cells and tissues. In: PLA. & S. E. A. (eds) Methods in cell biology: mitochondria (2nd ed., Vol. 80, pp. 155–171). Elsevier

  • Vonck J, Schafer E (2009) Supramolecular organization of protein complexes in the mitochondrial inner membrane. Biochim Biophys Acta 1793(1):117–124

    Article  CAS  Google Scholar 

  • Wang HJ, Pan YX, Wang WZ, Zucker IH, Wang W (2009) NADPH oxidase-derived reactive oxygen species in skeletal muscle modulates the exercise pressor reflex. J Appl Physiol 107(2):450–459

    Article  CAS  Google Scholar 

  • Webster HL, Williams JT (1964) The preparation and characterization of subcellular fractions of rat myocardium. Exp Cell Res 35:449–463

    Article  CAS  Google Scholar 

  • Wu F, Tyml K, Wilson JX (2008) iNOS expression requires NADPH oxidase-dependent redox signaling in microvascular endothelial cells. J Cell Physiol 217(1):207–214

    Article  CAS  Google Scholar 

  • Zapelini PH, Rezin GT, Cardoso MR, Ritter C, Klamt F, Moreira JC et al (2008) Antioxidant treatment reverses mitochondrial dysfunction in a sepsis animal model. Mitochondrion 8(3):211–218

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Free Radical Biology, School of Pharmacy and Biochemistry, University of Buenos Aires, Junín 956, C1113AAD, Buenos Aires, Argentina

    Virginia Vanasco, Natalia D. Magnani, María Cecilia Cimolai, Laura B. Valdez, Pablo Evelson, Alberto Boveris & Silvia Alvarez

Authors
  1. Virginia Vanasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Natalia D. Magnani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. María Cecilia Cimolai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laura B. Valdez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pablo Evelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alberto Boveris
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Silvia Alvarez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Silvia Alvarez.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vanasco, V., Magnani, N.D., Cimolai, M.C. et al. Endotoxemia impairs heart mitochondrial function by decreasing electron transfer, ATP synthesis and ATP content without affecting membrane potential. J Bioenerg Biomembr 44, 243–252 (2012). https://doi.org/10.1007/s10863-012-9426-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-012-9426-3

Keywords

Search

Navigation