Artículos de revistas
Effects Of Partial Inhibition Of Respiratory Complex I On H2o2 Production By Isolated Brain Mitochondria In Different Respiratory States
Neurochemical Research. Springer New York Llc, v. 39, n. 12, p. 2419 - 2430, 2014.
The aim of this work was to characterize the effects of partial inhibition of respiratory complex I by rotenone on H2O2 production by isolated rat brain mitochondria in different respiratory states. Flow cytometric analysis of membrane potential in isolated mitochondria indicated that rotenone leads to uniform respiratory inhibition when added to a suspension of mitochondria. When mitochondria were incubated in the presence of a low concentration of rotenone (10 nm) and NADH-linked substrates, oxygen consumption was reduced from 45.9 ± 1.0 to 26.4 ± 2.6 nmol O2 mg−1 min−1 and from 7.8 ± 0.3 to 6.3 ± 0.3 nmol O2 mg−1 min−1 in respiratory states 3 (ADP-stimulated respiration) and 4 (resting respiration), respectively. Under these conditions, mitochondrial H2O2 production was stimulated from 12.2 ± 1.1 to 21.0 ± 1.2 pmol H2O2 mg−1 min−1 and 56.5 ± 4.7 to 95.0 ± 11.1 pmol H2O2 mg−1 min−1 in respiratory states 3 and 4, respectively. Similar results were observed when comparing mitochondrial preparations enriched with synaptic or nonsynaptic mitochondria or when 1-methyl-4-phenylpyridinium ion (MPP+) was used as a respiratory complex I inhibitor. Rotenone-stimulated H2O2 production in respiratory states 3 and 4 was associated with a high reduction state of endogenous nicotinamide nucleotides. In succinate-supported mitochondrial respiration, where most of the mitochondrial H2O2 production relies on electron backflow from complex II to complex I, low rotenone concentrations inhibited H2O2 production. Rotenone had no effect on mitochondrial elimination of micromolar concentrations of H2O2. The present results support the conclusion that partial complex I inhibition may result in mitochondrial energy crisis and oxidative stress, the former being predominant under oxidative phosphorylation and the latter under resting respiration conditions.391224192430Braak, H., Ghebremedhin, E., Rüb, U., Bratzke, H., Del Tredici, K., Stages in the development of Parkinson’s disease-related pathology (2004) Cell Tissue Res, 318, pp. 121-134. , PID: 15338272Schapira, A.H., Cooper, J.M., Dexter, D., Jenner, P., Clark, J.B., Marsden, C.D., Mitochondrial complex I deficiency in Parkinson’s disease (1989) Lancet, 1, p. 1269. , COI: 1:STN:280:DyaL1M3mtVOktQ%3D%3D, PID: 2566813Schapira, A.H., Mann, V.M., Cooper, J.M., Dexter, D., Daniel, S.E., Jenner, P., Clark, J.B., Marsden, C.D., Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson’s disease (1990) J Neurochem, 55, pp. 2142-2145. , COI: 1:CAS:528:DyaK3MXpvFeltw%3D%3D, PID: 2121905Parker, W.D., Jr., Boyson, S.J., Parks, J.K., Abnormalities of the electron transport chain in idiopathic Parkinson’s disease (1989) Ann Neurol, 26, pp. 719-723. , PID: 2557792Schapira, A.H., Evidence for mitochondrial dysfunction in Parkinson’s disease—a critical appraisal (1994) Mov Disord, 9, pp. 125-138. , COI: 1:STN:280:DyaK2c3lsVyqug%3D%3D, PID: 8196673Bender, A., Krishnan, K.J., Morris, C.M., Taylor, G.A., Reeve, A.K., Perry, R.H., Jaros, E., Turnbull, D.M., High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease (2006) Nat Genet, 38, pp. 515-517. , COI: 1:CAS:528:DC%2BD28XjvVGksbs%3D, PID: 16604074Schon, E.A., DiMauro, S., Hirano, M., Human mitochondrial DNA: roles of inherited and somatic mutations (2012) Nat Rev Genet, 13, pp. 878-890. , COI: 1:CAS:528:DC%2BC38Xhs1OgsLfO, PID: 23154810Nicklas, W.J., Youngster, S.K., Kindt, M.V., Heikkila, R.E., MPTP, MPP+ and mitochondrial function (1987) Life Sci, 40, pp. 721-729. , COI: 1:CAS:528:DyaL2sXhtlehsbY%3D, PID: 3100899Langston, J.W., Ballard, P., Tetrud, J.W., Irwin, I., Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis (1983) Science, 219, pp. 979-980. , COI: 1:STN:280:DyaL3s7hvF2mtg%3D%3D, PID: 6823561Betarbet, R., Sherer, T.B., MacKenzie, G., Garcia-Osuna, M., Panov, A.V., Greenamyre, J.T., Chronic systemic pesticide exposure reproduces features of Parkinson’s disease (2000) Nat Neurosci, 3, pp. 1301-1306. , COI: 1:CAS:528:DC%2BD3cXosVGgsbg%3D, PID: 11100151Greenamyre, J.T., Cannon, J.R., Drolet, R., Mastroberardino, P.G., Lessons from the rotenone model of Parkinson’s disease (2010) Trends Pharmacol Sci, 31, pp. 141-142. , COI: 1:CAS:528:DC%2BC3cXjvFKksbw%3D, PID: 20096940Tapias, V., Cannon, J.R., Greenamyre, J.T., Melatonin treatment potentiates neurodegeneration in a rat rotenone Parkinson’s disease model (2010) J Neurosci Res, 88, pp. 420-427. , COI: 1:CAS:528:DC%2BD1MXhsFensb3K, PID: 19681169Sanders, L.H., Timothy Greenamyre, J., Oxidative damage to macromolecules in human Parkinson disease and the rotenone model (2013) Free Radic Biol Med, 62, pp. 111-120. , COI: 1:CAS:528:DC%2BC3sXivF2rtbY%3D, PID: 23328732Barrientos, A., Moraes, C.T., Titrating the effects of mitochondrial complex I impairment in the cell physiology (1999) J Biol Chem, 274, pp. 16188-16197. , COI: 1:CAS:528:DyaK1MXjs1Ons7s%3D, PID: 10347173Chinopoulos, C., Adam-Vizi, V., Mitochondria deficient in complex I activity are depolarized by hydrogen peroxide in nerve terminals: relevance to Parkinson’s disease (2001) J Neurochem, 76, pp. 302-306. , COI: 1:CAS:528:DC%2BD3MXhtVGltr0%3D, PID: 11146003Testa, C.M., Sherer, T.B., Greenamyre, J.T., Rotenone induces oxidative stress and dopaminergic neuron damage in organotypic substantia nigra cultures (2005) Brain Res Mol Brain Res, 134, pp. 109-118. , COI: 1:CAS:528:DC%2BD2MXisFGmur8%3D, PID: 15790535Yadava, N., Nicholls, D.G., Spare respiratory capacity rather than oxidative stress regulates glutamate excitotoxicity after partial respiratory inhibition of mitochondrial complex I with rotenone (2007) J Neurosci, 27, pp. 7310-7317. , COI: 1:CAS:528:DC%2BD2sXot1egtLc%3D, PID: 17611283Pöltl, D., Schildknecht, S., Karreman, C., Leist, M., Uncoupling of ATP-depletion and cell death in human dopaminergic neurons (2012) Neurotoxicology, 33, pp. 769-779. , PID: 22206971Surmeier, D.J., Schumacker, P.T., Calcium, bioenergetics, and neuronal vulnerability in Parkinson’s disease (2013) J Biol Chem, 288, pp. 10736-10741. , COI: 1:CAS:528:DC%2BC3sXlvFSiurc%3D, PID: 23086948Votyakova, T.V., Reynolds, I.J., DeltaPsi(m)-dependent and -independent production of reactive oxygen species by rat brain mitochondria (2001) J Neurochem, 79, pp. 266-277. , COI: 1:CAS:528:DC%2BD3MXnvFSmsrs%3D, PID: 11677254Liu, Y., Fiskum, G., Schubert, D., Generation of reactive oxygen species by the mitochondrial electron transport chain (2002) J Neurochem, 80, pp. 780-787. , COI: 1:CAS:528:DC%2BD38Xit1Gnu7Y%3D, PID: 11948241Sousa, S.C., Maciel, E.N., Vercesi, A.E., Castilho, R.F., Ca2+-induced oxidative stress in brain mitochondria treated with the respiratory chain inhibitor rotenone (2003) FEBS Lett, 543, pp. 179-183. , COI: 1:CAS:528:DC%2BD3sXjs1Crt7k%3D, PID: 12753929Tahara, E.B., Navarete, F.D., Kowaltowski, A.J., Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation (2009) Free Radic Biol Med, 46, pp. 1283-1297. , COI: 1:CAS:528:DC%2BD1MXkt1ShsL0%3D, PID: 19245829Starkov, A.A., Fiskum, G., Regulation of brain mitochondrial H2O2 production by membrane potential and NAD(P)H redox state (2003) J Neurochem, 86, pp. 1101-1107. , COI: 1:CAS:528:DC%2BD3sXmvFait7o%3D, PID: 12911618Kudin, A.P., Bimpong-Buta, N.Y., Vielhaber, S., Elger, C.E., Kunz, W.S., Characterization of superoxide-producing sites in isolated brain mitochondria (2004) J Biol Chem, 279, pp. 4127-4135. , COI: 1:CAS:528:DC%2BD2cXps12itg%3D%3D, PID: 14625276Sherer, T.B., Betarbet, R., Stout, A.K., Lund, S., Baptista, M., Panov, A.V., Cookson, M.R., Greenamyre, J.T., An in vitro model of Parkinson’s disease: linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage (2002) J Neurosci, 22, pp. 7006-7015. , COI: 1:CAS:528:DC%2BD38XmsF2gs7Y%3D, PID: 12177198Sipos, I., Tretter, L., Adam-Vizi, V., Quantitative relationship between inhibition of respiratory complexes and formation of reactive oxygen species in isolated nerve terminals (2003) J Neurochem, 84, pp. 112-118. , COI: 1:CAS:528:DC%2BD3sXhtF2iug%3D%3D, PID: 12485407Mirandola, S.R., Melo, D.R., Saito, A., Castilho, R.F., 3-nitropropionic acid-induced mitochondrial permeability transition: comparative study of mitochondria from different tissues and brain regions (2010) J Neurosci Res, 88, pp. 630-639. , COI: 1:CAS:528:DC%2BC3cXkvFGhsg%3D%3D, PID: 19795369Rosenthal, R.E., Hamud, F., Fiskum, G., Varghese, P.J., Sharpe, S., Cerebral ischemia and reperfusion: prevention of brain mitochondrial injury by lidoflazine (1987) J Cereb Blood Flow Metab, 7, pp. 752-758. , COI: 1:CAS:528:DyaL1cXhtVKitbo%3D, PID: 3693430Sims, N.R., Anderson, M.F., Isolation of mitochondria from rat brain using Percoll density gradient centrifugation (2008) Nat Protoc, 3, pp. 1228-1239. , COI: 1:CAS:528:DC%2BD1cXotFakur4%3D, PID: 18600228Sims, N.R., Rapid isolation of metabolically active mitochondria from rat brain and subregions using Percoll density gradient centrifugation (1990) J Neurochem, 55, pp. 698-707. , COI: 1:CAS:528:DyaK3cXltFWrt7c%3D, PID: 2164576Kaplan, R.S., Pedersen, P.L., Characterization of phosphate efflux pathways in rat liver mitochondria (1983) Biochem J, 212, pp. 279-288. , COI: 1:CAS:528:DyaL3sXktVWqs78%3D, PID: 6882372Mattiasson, G., Flow cytometric analysis of isolated liver mitochondria to detect changes relevant to cell death (2004) Cytom A, 60, pp. 145-154Robinson, J., Cooper, J.M., Method of determining oxygen concentrations in biological media, suitable for calibration of the oxygen electrode (1970) Anal Biochem, 33, pp. 390-399. , COI: 1:CAS:528:DyaE3cXoslSqsQ%3D%3D, PID: 4314758Tretter, L., Biagioni Angeli, E., Ardestani, M.R., Goracci, G., Adam-Vizi, V., Reversible inhibition of hydrogen peroxide elimination by calcium in brain mitochondria (2011) J Neurosci Res, 89, pp. 1965-1972. , COI: 1:CAS:528:DC%2BC3MXht1yktLjP, PID: 21541982Ronchi, J.A., Figueira, T.R., Ravagnani, F.G., Oliveira, H.C., Vercesi, A.E., Castilho, R.F., A spontaneous mutation in the nicotinamide nucleotide transhydrogenase gene of C57BL/6J mice results in mitochondrial redox abnormalities (2013) Free Radic Biol Med, 63, pp. 446-456. , COI: 1:CAS:528:DC%2BC3sXhtFyjsbnM, PID: 23747984Long, J., Ma, J., Luo, C., Mo, X., Sun, L., Zang, W., Liu, J., Comparison of two methods for assaying complex I activity in mitochondria isolated from rat liver, brain and heart (2009) Life Sci, 85, pp. 276-280. , COI: 1:CAS:528:DC%2BD1MXptlSquro%3D, PID: 19520091Navarro, A., Bández, M.J., Gómez, C., Repetto, M.G., Boveris, A., Effects of rotenone and pyridaben on complex I electron transfer and on mitochondrial nitric oxide synthase functional activity (2010) J Bioenerg Biomembr, 42, pp. 405-412. , COI: 1:CAS:528:DC%2BC3cXhsVKkt7rF, PID: 20886364Agarwal, B., Dash, R.K., Stowe, D.F., Bosnjak, Z.J., Camara, A.K., Isoflurane modulates cardiac mitochondrial bioenergetics by selectively attenuating respiratory complexes (2014) Biochim Biophys Acta, 1837, pp. 354-365. , COI: 1:CAS:528:DC%2BC2cXhs1Gqt7g%3D, PID: 24355434Aiuchi, T., Shirane, Y., Kinemuchi, H., Arai, Y., Nakaya, K., Nakamura, Y., Enhancement by tetraphenylboron of inhibition of mitochondrial respiration induced by 1-methyl-4-phenylpyridinium ion (MPP+) (1988) Neurochem Int, 12, pp. 525-531. , COI: 1:CAS:528:DyaL1cXksV2qs7s%3D, PID: 20501261Ramsay, R.R., Mehlhorn, R.J., Singer, T.P., Enhancement by tetraphenylboron of the interaction of the 1-methyl-4-phenylpyridinium ion (MPP+) with mitochondria (1989) Biochem Biophys Res Commun, 159, pp. 983-990. , COI: 1:CAS:528:DyaL1MXitVOgu7c%3D, PID: 2784681Chinta, S.J., Rane, A., Yadava, N., Andersen, J.K., Nicholls, D.G., Polster, B.M., Reactive oxygen species regulation by AIF- and complex I-depleted brain mitochondria (2009) Free Radic Biol Med, 46, pp. 939-947. , COI: 1:CAS:528:DC%2BD1MXivVKgtbc%3D, PID: 19280713Gyulkhandanyan, A.V., Pennefather, P.S., Shift in the localization of sites of hydrogen peroxide production in brain mitochondria by mitochondrial stress (2004) J Neurochem, 90, pp. 405-421. , COI: 1:CAS:528:DC%2BD2cXmtVyrt78%3D, PID: 15228597Figueira, T.R., Barros, M.H., Camargo, A.A., Castilho, R.F., Ferreira, J.C., Kowaltowski, A.J., Sluse, F.E., Vercesi, A.E., Mitochondria as a source of reactive oxygen and nitrogen species: from molecular mechanisms to human health (2013) Antioxid Redox Signal, 18, pp. 2029-2074. , COI: 1:CAS:528:DC%2BC3sXmtVyhs78%3D, PID: 23244576Korshunov, S.S., Skulachev, V.P., Starkov, A.A., High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria (1997) FEBS Lett, 416, pp. 15-18. , COI: 1:CAS:528:DyaK2sXms1eksro%3D, PID: 9369223Petrosillo, G., Ruggiero, F.M., Paradies, G., Role of reactive oxygen species and cardiolipin in the release of cytochrome c from mitochondria (2003) FASEB J, 17, pp. 2202-2208. , COI: 1:CAS:528:DC%2BD3sXpvVSmtr0%3D, PID: 14656982Zoccarato, F., Cavallini, L., Alexandre, A., Respiration-dependent removal of exogenous H2O2 in brain mitochondria: inhibition by Ca2+ (2004) J Biol Chem, 279, pp. 4166-4174. , COI: 1:CAS:528:DC%2BD2cXps12iuw%3D%3D, PID: 14634020Lopert, P., Patel, M., Nicotinamide nucleotide transhydrogenase (Nnt) links the substrate requirement in brain mitochondria for hydrogen peroxide removal to the thioredoxin/peroxiredoxin (Trx/Prx) system (2014) J Biol Chem, 289, pp. 15611-15620. , COI: 1:CAS:528:DC%2BC2cXovVehu7Y%3D, PID: 24722990Rossignol, R., Malgat, M., Mazat, J.P., Letellier, T., Threshold effect and tissue specificity. Implication for mitochondrial cytopathies (1999) J Biol Chem, 274, pp. 33426-33432. , COI: 1:CAS:528:DyaK1MXns1ejsr4%3D, PID: 10559224Chan, C.S., Guzman, J.N., Ilijic, E., Mercer, J.N., Rick, C., Tkatch, T., Meredith, G.E., Surmeier, D.J., ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease (2007) Nature, 447, pp. 1081-1086. , COI: 1:CAS:528:DC%2BD2sXmvFKmurY%3D, PID: 17558391Fahn, S., Cohen, G., The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it (1992) Ann Neurol, 32, pp. 804-812. , COI: 1:STN:280:DyaK3s7htFOjtQ%3D%3D, PID: 1471873Jenner, P., Dexter, D.T., Sian, J., Schapira, A.H., Marsden, C.D., Oxidative stress as a cause of nigral cell death in Parkinson’s disease and incidental Lewy body disease. The Royal Kings and Queens Parkinson’s Disease Research Group (1992) Ann Neurol, 32, pp. S82-S87. , COI: 1:CAS:528:DyaK3sXnvVSntQ%3D%3D, PID: 1510385Camara, A.K., Lesnefsky, E.J., Stowe, D.F., Potential therapeutic benefits of strategies directed to mitochondria (2010) Antioxid Redox Signal, 13, pp. 279-347. , COI: 1:CAS:528:DC%2BC3cXnvV2ku7s%3D, PID: 20001744Perfeito, R., Cunha-Oliveira, T., Rego, A.C., Reprint of: revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease-resemblance to the effect of amphetamine drugs of abuse (2013) Free Radic Biol Med, 62, pp. 186-201. , COI: 1:CAS:528:DC%2BC3sXhtFCkt7nI, PID: 23743292Brand, M.D., The sites and topology of mitochondrial superoxide production (2010) Exp Gerontol, 2010 (45), pp. 466-472Ramsay, R.R., Krueger, M.J., Youngster, S.K., Gluck, M.R., Casida, J.E., Singer, T.P., Interaction of 1-methyl-4-phenylpyridinium ion (MPP+) and its analogs with the rotenone/piericidin binding site of NADH dehydrogenase (1991) J Neurochem, 56, pp. 1184-1190. , COI: 1:CAS:528:DyaK3MXitVWgs74%3D, PID: 2002336Gerlach, M., Riederer, P., Przuntek, H., Youdim, M.B., MPTP mechanisms of neurotoxicity and their implications for Parkinson’s disease (1991) Eur J Pharmacol, 208, pp. 273-286. , COI: 1:CAS:528:DyaK38Xnslylsg%3D%3D, PID: 1815982Tipton, K.F., Singer, T.P., Advances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds (1993) J Neurochem, 61, pp. 1191-1206. , COI: 1:CAS:528:DyaK3sXms1Chsrg%3D, PID: 8376979Bajpai, P., Sangar, M.C., Singh, S., Tang, W., Bansal, S., Chowdhury, G., Cheng, Q., Avadhani, N.G., Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by mitochondrion-targeted cytochrome P450 2D6: implications in Parkinson disease (2013) J Biol Chem, 288, pp. 4436-4451. , COI: 1:CAS:528:DC%2BC3sXit1Krtrk%3D, PID: 23258538Hattori, N., Tanaka, M., Ozawa, T., Mizuno, Y., Immunohistochemical studies on complexes I, II, III, and IV of mitochondria in Parkinson’s disease (1991) Ann Neurol, 30, pp. 563-571. , COI: 1:STN:280:DyaK387mtFOntg%3D%3D, PID: 1665052McNaught, K.S., Jenner, P., Altered glial function causes neuronal death and increases neuronal susceptibility to 1-methyl-4-phenylpyridinium- and 6-hydroxydopamine-induced toxicity in astrocytic/ventral mesencephalic co-cultures (1999) J Neurochem, 73, pp. 2469-2476. , COI: 1:CAS:528:DyaK1MXns1ehu7s%3D, PID: 10582607Schapira, A.H., Mitochondrial involvement in Parkinson’s disease, Huntington’s disease, hereditary spastic paraplegia and Friedreich’s ataxia (1999) Biochim Biophys Acta, 1410, pp. 159-170. , COI: 1:STN:280:DyaK1M7nslCltA%3D%3D, PID: 10076024Brown, M.R., Sullivan, P.G., Geddes, J.W., Synaptic mitochondria are more susceptible to Ca2+ overload than nonsynaptic mitochondria (2006) J Biol Chem, 281, pp. 11658-11668. , COI: 1:CAS:528:DC%2BD28Xjslegur0%3D, PID: 16517608Naga, K.K., Sullivan, P.G., Geddes, J.W., High cyclophilin D content of synaptic mitochondria results in increased vulnerability to permeability transition (2007) J Neurosci, 27, pp. 7469-7475. , COI: 1:CAS:528:DC%2BD2sXnvFyhurs%3D, PID: 17626207Lores-Arnaiz, S., Bustamante, J., Age-related alterations in mitochondrial physiological parameters and nitric oxide production in synaptic and non-synaptic brain cortex mitochondria (2011) Neuroscience, 188, pp. 117-124. , COI: 1:CAS:528:DC%2BC3MXnslKhtrk%3D, PID: 21600964Davey, G.P., Clark, J.B., Threshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria (1996) J Neurochem, 66, pp. 1617-1624. , COI: 1:CAS:528:DyaK28XhslGhsL8%3D, PID: 8627318Davey, G.P., Peuchen, S., Clark, J.B., Energy thresholds in brain mitochondria. Potential involvement in neurodegeneration (1998) J Biol Chem, 273, pp. 12753-12757. , COI: 1:CAS:528:DyaK1cXjsVertb4%3D, PID: 9582300Cino, M., Del Maestro, R.F., Generation of hydrogen peroxide by brain mitochondria: the effect of reoxygenation following postdecapitative ischemia (1989) Arch Biochem Biophys, 269, pp. 623-638. , COI: 1:CAS:528:DyaL1MXhtlejtb4%3D, PID: 2919886Pryde, K.R., Hirst, J., Superoxide is produced by the reduced flavin in mitochondrial complex I: a single, unified mechanism that applies during both forward and reverse electron transfer (2011) J Biol Chem, 286, pp. 18056-18065. , COI: 1:CAS:528:DC%2BC3MXmtVGju7s%3D, PID: 21393237Treberg, J.R., Quinlan, C.L., Brand, M.D., Evidence for two sites of superoxide production by mitochondrial NADH-ubiquinone oxidoreductase (complex I) (2011) J Biol Chem, 286, pp. 27103-27110. , COI: 1:CAS:528:DC%2BC3MXpsVOnt78%3D, PID: 21659507Orr, A.L., Ashok, D., Sarantos, M.R., Shi, T., Hughes, R.E., Brand, M.D., Inhibitors of ROS production by the ubiquinone-binding site of mitochondrial complex I identified by chemical screening (2013) Free Radic Biol Med, 65C, pp. 1047-1059Vesce, S., Kirk, L., Nicholls, D.G., Relationships between superoxide levels and delayed calcium deregulation in cultured cerebellar granule cells exposed continuously to glutamate (2004) J Neurochem, 90, pp. 683-693. , COI: 1:CAS:528:DC%2BD2cXmsFertrY%3D, PID: 15255947Sousa, S.C., Castilho, R.F., Protective effect of melatonin on rotenone plus Ca2+-induced mitochondrial oxidative stress and PC12 cell death (2005) Antioxid Redox Signal, 7, pp. 1110-1116. , COI: 1:CAS:528:DC%2BD2MXos1eqsr4%3D, PID: 16115015Berndt, N., Holzhütter, H.G., Bulik, S., Implications of enzyme deficiencies on the mitochondrial energy metabolism and ROS formation of neurons involved in rotenone-induced Parkinson’s disease: A model-based analysis (2013) FEBS J, 280, pp. 5080-5093. , COI: 1:CAS:528:DC%2BC3sXhsFOgsr3F, PID: 23937586