Preferences help
enabled [disable] Abstract
Number of results
2010 | 57 | 4 | 435-441
Article title

Mitochondrial respiratory chain inhibitors modulate the metal-induced inner mitochondrial membrane permeabilization

Title variants
Languages of publication
To elucidate the molecular mechanisms of the protective action of stigmatellin (an inhibitor of complex III of mitochondrial electron transport chain, mtETC) against the heavy metal-induced cytotoxicity, we tested its effectiveness against mitochondrial membrane permeabilization produced by heavy metal ions Cd2+, Hg2+, Cu2+ and Zn2+, as well as by Ca2+ (in the presence of Pi) or Se (in form of Na2SeO3) using isolated rat liver mitochondria. It was shown that stigmatellin modulated mitochondrial swelling produced by these metals/metalloids in the isotonic sucrose medium in the presence of ascorbate plus tetramethyl-p-phenylenediamine (complex IV substrates added for energization of the mitochondria). It was found that stigmatellin and other mtETC inhibitors enhanced the mitochondrial swelling induced by selenite. However, in the same medium, all the mtETC inhibitors tested as well as cyclosporin A and bongkrekic acid did not significantly affect Cu2+-induced swelling. In contrast, the high-amplitude swelling produced by Cd2+, Hg2+, Zn2+, or Ca2+ plus Pi was significantly depressed by these inhibitors. Significant differences in the action of these metals/metalloids on the redox status of pyridine nucleotides, transmembrane potential and mitochondrial respiration were also observed. In the light of these results as well as the data from the recent literature, our hypothesis on a possible involvement of the respiratory supercomplex, formed by complex I (P-site) and complex III (S-site) in the mitochondrial permeabilization mediated by the mitochondrial transition pore, is updated.
Physical description
  • Laboratory of Comparative Biochemistry of Inorganic Ions, I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St.-Petersburg, Russia
  • Al-Nasser IA (2000) Cadmium hepatotoxicity and alterations of the mitochondrial function. J Toxicol Clin Toxicol 38: 407-413.
  • Allshire A, Bernardi P, Saris N-E (1985) Manganese stimulates calcium flux through the mitochondrial uniporter. Biochim Biophys Acta 807: 202-209.
  • Belyaeva EA, Glazunov VV, Nikitina ER, Korotkov SM (2001) Bivalent metal ions modulate Cd2+ effects on isolated rat liver mitochondria. J Bioenerg Biomembr 33: 303-318.
  • Belyaeva EA, Glazunov VV, Korotkov SM (2002) Cyclosporin A-sensitive permeability transition pore is involved in Cd2+-induced dysfunction of isolated rat liver mitochondria: doubts no more. Arch Biochem Biophys 405: 252-264.
  • Belyaeva EA, Korotkov SM (2003) Mechanism of primary Cd2+-induced rat liver mitochondria dysfunction: discrete modes of Cd2+ action on calcium and thiol-dependent domains. Toxicol Appl Pharmacol 192: 56-68.
  • Belyaeva EA (2004a) Regulated mitochondrial permeability transition: a possible involvement of mitochondrial respiratory complexes I and III. Mitochondrion 4: 71.
  • Belyaeva EA, Glazunov VV, Korotkov SM (2004b) Cd2+-promoted mitochondrial permeability transition: a comparison with other heavy metals. Acta Biochim Pol 51: 545-551.
  • Belyaeva EA, Glazunov VV, Korotkov SM (2004) Cd2+ versus Ca2+-produced mitochondrial membrane permeabilization: a proposed direct participation of respiratory complexes I and III. Chem-Biol Interact 150: 253-270.
  • Belyaeva EA, Dymkowska D, Więckowski MR, Wojtczak L (2006) Reactive oxygen species produced by the mitochondrial respiratory chain are involved in Cd2+-induced injury of rat ascites hepatoma AS-30D cells. Biochim Biophys Acta 1757: 1568-1574.
  • Belyaeva EA, Dymkowska D, Więckowski MR, Wojtczak L (2008) Mitochondria as an important target in heavy metal toxicity in rat hepatoma AS-30D cells. Toxicol Appl Pharmacol 231: 34-42.
  • Belyaeva EA, Saris N-E (2008) Cd2+-produced disturbance of mitochondrial function: the cause/consequence relationships. In Metal ions in biology and medicine. Collery P, Maymard I, Theophanides T, Khassanova L, Collery T, eds, vol 10, pp 328-333. John Libbey Eurotext, Paris.
  • Chávez E, Zazueta C, Díaz E, Holquín JA (1989) Characterization by Hg2+ of two different pathways for mitochondrial Ca2+ release. Biochim Biophys Acta 986: 27-32.
  • Devinney MJ, Malaiyandi LM, Vergun O, De Franco DB, Hastings TG, Dineley KE (2009) A comparison of Zn2+- and Ca2+-triggered depolarization of liver mitochondria reveals no evidence of Zn2+-induced permeability transition. Cell Calcium 45: 447-455.
  • Dierks T, Salentin A, Krämer R (1990a) Pore-like and carrier-like properties of the mitochondrial aspartate/glutamate carrier after modification by SH-reagents: evidence for a performed channel as a structural requirement of carrier-mediated transport. Biochim Biophys Acta 1028: 281-288.
  • Dierks T, Salentin A, Heberger C, Krämer R (1990b) The mitochondrial aspartate/glutamate and ADP/ATP carrier switch from obligate counterexchange to unidirectional transport after modification by SH-reagents. Biochim Biophys Acta 1028: 268-280.
  • Dineley KE, Votyakova TV, Reynolds IJ (2003) Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration. J Neurochem 85: 563-570.
  • Koike H, Shinohara Y, Terada H (1991) Why is inorganic phosphate necessary for uncoupling of oxidative phosphorylation by Cd2+ in rat liver mitochondria? Biochim Biophys Acta 1060: 75-81.
  • Dorta DJ, Leite S, De Marco KC, Prado IM, Rodrigues T, Mingato FE, Uyemura SA, Santos AC, Curti C (2003) A proposed sequence of events for cadmium-induced mitochondrial impairment. J Inorg Biochem 97: 251- 257.
  • Fontaine E, Bernardi P (1999) Progress on the mitochondrial pore: regulation by complex I and ubiquinone analogs. J Bioenerg Biomembr 31: 335-345.
  • García N, Zazueta C, Carrillo R, Correa F, Chávez E (2000) Copper sensitizes the mitochondrial permeability transition to carboxytractyloside and oleate. Mol Cell Biochem 209: 119-123.
  • Gazaryan IG, Krasinskaya IP, Kristal BS, Brown AM (2007) Zinc irreversibly damages major enzymes of energy production and antioxidant defense prior to mitochondrial permeability transition. J Biol Chem 282: 24373-24380.
  • Halestrap AP (2009) What is the mitochondrial permeability transition pore? J Mol Cell Cardiol 46: 821-831.
  • He L, Lemasters JJ (2002) Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function? FEBS Lett 512: 1-7.
  • He L, Lemasters JJ (2005) Dephosphorylation of the Rieske iron-sulfur protein after induction of the mitochondrial permeability transition. Biochem Biophys Res Commun 334: 829-837.
  • Jiang D, Sullivan PG, Sensi SL, Steward O, Weiss JH (2001) Zn(2+) induces permeability transition pore opening and release of pro-apoptotic peptides from neuronal mitochondria. J Biol Chem 276: 47524-47529.
  • Kim T-S, Jeong D-W, Yun BY, Kim IY (2002) Dysfunction of rat liver mitochondria by selenite: induction of mitochondrial permeability transition through thiol-oxidation. Biochem Biophys Res Commun 294: 1130-1137.
  • Kim T-S, Yun BY, Kim IY (2003) Induction of the mitochondrial permeability transition by selenium compounds mediated by oxidation of the protein thiol groups and generation of the superoxide. Biochem Pharmacol 66: 2301-2311.
  • Leblondel G, Allain P (1984) A thiol oxidation interpretation of the Cu2+ effects on rat liver mitochondria. J Inorg Biochem 21: 241-251.
  • Lee WK, Bork U, Gholamrezaei F, Thévenod F (2005a) Cd(2+)-induced cytochrome c release in apoptotic proximal tubule cells: role of mitochondrial permeability transition pore and Ca(2+) uniporter. Am J Physiol Renal Physiol 288: F27-F39.
  • Lee WK, Spielmann M, Bork U, Thévenod F (2005b) Cd2+-induced swelling-contraction dynamics in isolated kidney cortex mitochondria: role of Ca2+ uniporter, K+ cycling, and protonmotive force. Am J Physiol Cell Physiol 289: C656-C664.
  • Lemasters JJ, Theruvath TP, Zhong Z, Nieminen AL (2009) Mitochondrial calcium and the permeability transition in cell death. Biochim Biophys Acta 1787: 1395-1401.
  • Lenaz G, Baracca A, Barbero G, Bergamini C, Dalmonte ME, Del Sole M, Faccioli M, Falasca A, Fato R, Genova ML, Sgarbi G, Solaini G (2010) Mitochondrial respiratory chain super-complex I-III in physiology and pathology. Biochim Biophys Acta 1797: 633-640.
  • Nordberg GF (2009) Historical perspectives on cadmium toxicology. Toxicol Appl Pharmacol 238: 192-200.
  • Petronilli V, Sileikyte J, Zulian A, Dabbeni-Sala F, Jori G, Gobbo S, Tognon G, Nikolov P, Bernardi P, Ricchelli F (2009) Switch from inhibition to activation of the mitochondrial permeability transition during hematoporphyrin-mediated photooxidative stress. Unmasking pore-regulating external thiols. Biochim Biophys Acta 1787: 897-904.
  • Schroers A, Krämer R, Wohlrab H (1997) The reversible antiport-uniport conversion of the phosphate carrier from yeast mitochondria depends on the presence of a single cysteine. J Biol Chem 272: 10558-10564.
  • Shilo S, Tirosh O (2003) Selenite activates caspase-independent necrotic cell death in Jurkat T cells and J774.2 macrophages by affecting mitochondrial oxidant generation. Antioxid Redox Signal 5: 273-279.
  • Shilo S, Aronis A, Komarnitsky R, Tirosh O (2003) Selenite sensitizes mitochondrial permeability transition pore opening in vitro and in vivo: a possible mechanism for chemo-protection. Biochem J 370: 283-290.
  • Stohs SJ, Bagchi D (1995) Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med 18: 321-336.
  • Valko M, Morris H, Cronin MT (2005) Metals, toxicity and oxidative stress. Curr Med Chem 12: 1161-208.
  • Waalkes MP (2003) Cadmium carcinogenesis. Mutat Res 533: 107-120.
  • Waisberg M, Joseph P, Hale B, Beyersmann D (2003) Molecular and cellular mechanisms of cadmium carcinogenesis. Toxicology 192: 95-117.
  • Wudarczyk J, Debska E, Lenartowicz E (1999) Zinc as an inducer of the membrane permeability transition in rat liver mitochondria. Arch Biochem Biophys 363: 1-8.
  • Zazueta C, Reyes-Vivas H, Zafra G, Sánchez CA, Vera G, Chávez E (1998) Mitochondrial permeability transition as induced by cross-linking of the adenine nucleotide translocase. Int J Biochem Cell Biol 30: 517-527.
  • Zazueta C, Sánchez C, García N, Correa F (2000) Possible involvement of the adenine nucleotide translocase in the activation of the permeability transition pore induced by cadmium. Int J Biochem Cell Biol 32: 1093-1101.
  • Zoratti M, Szabo I (1995) The mitochondrial permeability transition. Biochim Biophys Acta 1241: 139-176.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.