| | Molecular Initiating Event |
| | Chloroform → increased ROS | (1) Chiu, C.-H., et al. Chloroform extract of solanum lyratum induced G0/G1 arrest via p21/p16 and induced apoptosis via reactive oxygen species, caspases and mitochondrial pathways in human oral cancer cell lines. The American journal of Chinese medicine 43.07 (2015): 1453.
(2) Zhang, Y., et al. Chemical compositions and antiproliferation activities of the chloroform fraction from P. fomentarius in K562 cells. Human & experimental toxicology 34.7 (2015): 732.
(3) Wang, Y., et al. Investigating migration inhibition and apoptotic effects of Fomitopsis pinicola chloroform extract on human colorectal cancer SW-480 cells. PloS one 9.7 (2014): e101303.
(4) Looi, C.Y., et al. Induction of apoptosis in melanoma A375 cells by a chloroform fraction of Centratherum anthelminticum (L.) seeds involves NF-kappaB, p53 and Bcl-2-controlled mitochondrial signaling pathways. BMC complementary and alternative medicine 13.1 (2013): 166.
(5) Faustino‐Rocha, A.I., et al. Trihalomethanes in liver pathology: Mitochondrial dysfunction and oxidative stress in the mouse. Environmental toxicology 31.8 (2016): 1009.
(6) Ali, A., et al. Effect of drinking water disinfection by-products in human peripheral blood lymphocytes and sperm. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 770 (2014): 136.
(7) Brunner, E.A., et al. Effects of anesthesia on intermediary metabolism. Annual review of medicine 26.1 (1975): 391. |
| | Chloroform → decreased ATP | (1) Faustino‐Rocha, A. I., et al. Trihalomethanes in liver pathology: Mitochondrial dysfunction and oxidative stress in the mouse. Environmental toxicology 31.8 (2016): 1009.
(2) Rottenberg, H. Uncoupling of oxidative phosphorylation in rat liver mitochondria by general anesthetics. Proceedings of the National Academy of Sciences 80.11 (1983): 3313.
(3) Brunner, E.A., et al. Effects of anesthesia on intermediary metabolism. Annual review of medicine 26.1 (1975): 391. |
| | Chloroform → decreased glutathione (GSH) | (1) Ekström, T., et al. Chloroform-induced glutathione depletion and toxicity in freshly isolated hepatocytes. Biochemical pharmacology 29.22 (1980): 3059.
(2) Docks, E. L., et al. The role of glutathione in chloroform-induced hepatotoxicity. Experimental and molecular pathology 24.1 (1976): 13.
(3) Beddowes, E.J., et al. Chloroform, carbon tetrachloride and glutathione depletion induce secondary genotoxicity in liver cells via oxidative stress. Toxicology 187.2-3 (2003): 101.
(4) Wang, Y., et al. Investigating migration inhibition and apoptotic effects of Fomitopsis pinicola chloroform extract on human colorectal cancer SW-480 cells. PloS one 9.7 (2014): e101303.
(5) Abbassi, R., et al. Chloroform-induced oxidative stress in rat liver: implication of metallothionein. Toxicology and industrial health 26.8 (2010): 487.
(6) Hewitt, W.R., et al. Nephrotoxic interactions between ketonic solvents and halogenated aliphatic chemicals. Toxicological Sciences 4.6 (1984): 902.
(7) Skrzypińska-Gawrysiak, M., et al. The hepatotoxic action of chloroform: short-time dynamics of biochemical alterations and dose-effect relationships. Polish journal of occupational medicine and environmental health 4.1 (1991): 77.
(8) Azri-Meehan, S., et al. The hepatotoxicity of chloroform in precision-cut rat liver slices. Toxicology 73.3 (1992): 239.
(9) Ekström, T., et al. Lipid peroxidation in vivo monitored as ethane exhalation and malondialdehyde excretion in urine after oral administration of chloroform. Basic & Clinical Pharmacology & Toxicology 58.4 (1986): 289.
(10) Qin, L.-Q., et al. One-day dietary restriction changes hepatic metabolism and potentiates the hepatotoxicity of carbon tetrachloride and chloroform in rats. The Tohoku journal of experimental medicine 212.4 (2007): 379.
(11) Cohen, P.J., et al. Continuous in vivo measurement of hepatic lipoperoxidation using chemiluminescence: halothane and chloroform compared. Anesthesia and analgesia 70.3 (1990): 296. |
| | Chlorophenol → increased ROS | (1) Luo, Y., et al. 2-Chlorophenol induced hydroxyl radical production in mitochondria in Carassius auratus and oxidative stress–An electron paramagnetic resonance study. Chemosphere 71.7 (2008): 1260.
(2) Luo, Y., et al. 2-Chlorophenol induced ROS generation in fish Carassius auratus based on the EPR method. Chemosphere 65.6 (2006): 1064.
(3) Khachatryan, L., et al. Environmentally persistent free radicals (EPFRs). 1. Generation of reactive oxygen species in aqueous solutions. Environmental science & technology 45.19 (2011): 8559.
(4) Atkinson, A., et al. Increased oxidative stress in the liver of mice treated with trichloroethylene. Biochemistry and molecular biology international 31.2 (1993): 297.
(5) Igbinosa, E.O., et al. Toxicological profile of chlorophenols and their derivatives in the environment: the public health perspective. The Scientific World Journal (2013).
(6) Bukowska, B., et al. Comparison of the effect of phenol and its derivatives on protein and free radical formation in human erythrocytes (in vitro). Blood Cells, Molecules, and Diseases 39.3 (2007): 238.
(7) Michalowicz, J., et al. The Effects of 2, 4, 5-Trichlorophenol on Some Antioxidative Parameters and the Activity of Glutathione S-Transferase in Reed Canary Grass Leaves (Phalaris arudinacea). Polish Journal of Environmental Studies 18.5 (2009).
(8) Li, Z., et al. Stress responses to trichlorophenol in Arabidopsis and integrative analysis of alteration in transcriptional profiling from microarray. Gene 555.2 (2015): 159.
(9) Li, F., et al. Hydroxyl radical generation and oxidative stress in Carassius auratus liver as affected by 2, 4, 6-trichlorophenol. Chemosphere 67.1 (2007): 13.
(10) Xia, Xi., et al. Response of selenium-dependent glutathione peroxidase in the freshwater bivalve Anodonta woodiana exposed to 2, 4-dichlorophenol, 2, 4, 6-trichlorophenol and pentachlorophenol. Fish & shellfish immunology 55 (2016): 499.
(11) Dong, Y.-L., et al. Induction of oxidative stress and apoptosis by pentachlorophenol in primary cultures of Carassius carassius hepatocytes. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 150.2 (2009): 179. |
| | Chlorophenol → decreased ATP | (1) Aschmann, C., et al. Short-term effects of chlorophenols on the function and viability of primary cultured rat hepatocytes. Archives of toxicology 63.2 (1989): 121.
(2) Stockdale, M., et al. Effects of ring substituents on the activity of phenols as inhibitors and uncouplers of mitochondrial respiration. The FEBS Journal 21.4 (1971): 565.
(3) Mitsuda, H., et al. Effect of chlorophenol analogues on the oxidative phosphorylation in rat liver mitochondria. Agricultural and Biological Chemistry 27.5 (1963): 366.
(4) Stockdale, M., et al. Influence of ring substituents on the action of phenols on some dehydrogenases, phosphokinases and the soluble ATPase from mitochondria. The FEBS Journal 21.3 (1971): 416.
(5) Hugül, M., et al. Modeling the kinetics of UV/hydrogen peroxide oxidation of some mono-, di-, and trichlorophenols. Journal of hazardous materials 77.1-3 (2000): 193.
(6) Juhl, U., et al. The Induction of Dna Srtrand Breaks and Formation of Semiquinone Radicals by Metabolites of 2, 4, 5-Trichlorophenol. Free radical research communications 11.6 (1991): 295. |
| | Chlorophenol → decreased glutathione | (1) Li, F., et al. Hydroxyl radical generation and oxidative stress in Carassius auratus liver as affected by 2, 4, 6-trichlorophenol. Chemosphere 67.1 (2007): 13.
(2) Dong, Y.-L., et al. Induction of oxidative stress and apoptosis by pentachlorophenol in primary cultures of Carassius carassius hepatocytes. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 150.2 (2009): 179.
(3) Wang, Y.-J., et al. Induction of glutathione depletion, p53 protein accumulation and cellular transformation by tetrachlorohydroquinone, a toxic metabolite of pentachlorophenol. Chemico-biological interactions 105.1 (1997): 1.
(4) Valentovic, M., et al. 2-Amino-5-chlorophenol toxicity in renal cortical slices from Fischer 344 rats: effect of antioxidants and sulfhydryl agents. Toxicology and applied pharmacology 161.1 (1999): 1.
(5) Luo, Y., et al. 2-Chlorophenol induced hydroxyl radical production in mitochondria in Carassius auratus and oxidative stress–An electron paramagnetic resonance study. Chemosphere 71.7 (2008): 1260.
(6) Götz, R., et al. Effects of pentachlorophenol and 2, 4, 6-trichlorophenol on the disposition of sulfobromophthalein and respiration of isolated liver cells. Archives of toxicology 44.1-3 (1980): 147.
(7) Ahammed, G.J., et al. 24-Epibrassinolide alleviates organic pollutants-retarded root elongation by promoting redox homeostasis and secondary metabolism in Cucumis sativus L. Environmental Pollution 229 (2017): 922. |
| | Chloroacetic acid → increased ROS | (1) Lu, T.-H., et al. Chloroacetic acid triggers apoptosis in neuronal cells via a reactive oxygen species-induced endoplasmic reticulum stress signaling pathway. Chemico-biological interactions 225 (2015): 1.
(2) Chen, C.-H., et al. Chloroacetic acid induced neuronal cells death through oxidative stress-mediated p38-MAPK activation pathway regulated mitochondria-dependent apoptotic signals. Toxicology 303 (2013): 72.
(3) Pals, J., et al. Human cell toxicogenomic analysis linking reactive oxygen species to the toxicity of monohaloacetic acid drinking water disinfection byproducts. Environmental science & technology 47.21 (2013): 12514.
(4) Pals, J., et al. Biological mechanism for the toxicity of haloacetic acid drinking water disinfection byproducts. Environmental science & technology 45.13 (2011): 5791.
(5) Yin, J., et al. Comparative toxicity of chloro-and bromo-nitromethanes in mice based on a metabolomic method. Chemosphere 185 (2017): 20.
(6) Ali, A., et al. Effect of drinking water disinfection by-products in human peripheral blood lymphocytes and sperm. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 770 (2014): 136.
(7) Marsà, A., et al. Hazard assessment of three haloacetic acids, as byproducts of water disinfection, in human urothelial cells. Toxicology and applied pharmacology 347 (2018): 70.
(8) Zhang, X., et al. 2, 4, 6-Trichlorophenol cytotoxicity involves oxidative stress, endoplasmic reticulum stress, and apoptosis. International journal of toxicology 33.6 (2014): 532.
(9) Celik, I., et al. Hepatoprotective role and antioxidant capacity of pomegranate (Punica granatum) flowers infusion against trichloroacetic acid-exposed in rats. Food and Chemical Toxicology 47.1 (2009): 145.
(10) Dad, A., et al. Pyruvate remediation of cell stress and genotoxicity induced by haloacetic acid drinking water disinfection by‐products. Environmental and molecular mutagenesis 54.8 (2013): 629.
(11) Dad, A., et al. Haloacetic Acid Water Disinfection Byproducts Affect Pyruvate Dehydrogenase Activity and Disrupt Cellular Metabolism. Environmental science & technology 52.3 (2018): 1525. |
| | Chloroacetic acid → decreased ATP | (1) Dad, A., et al. Pyruvate remediation of cell stress and genotoxicity induced by haloacetic acid drinking water disinfection by‐products. Environmental and molecular mutagenesis 54.8 (2013): 629.
(2) Dad, A., et al. Haloacetic Acid Water Disinfection Byproducts Affect Pyruvate Dehydrogenase Activity and Disrupt Cellular Metabolism. Environmental science & technology 52.3 (2018): 1525.
(3) Schmidt, M., et al. Effects of chlorinated acetates on the glutathione metabolism and on glycolysis of cultured astrocytes. Neurotoxicity research 19.4 (2011): 628. |
| | Chloroacetic acid → decreased glutathione | (1) Chen, C.-H., et al. Chloroacetic acid induced neuronal cells death through oxidative stress-mediated p38-MAPK activation pathway regulated mitochondria-dependent apoptotic signals. Toxicology 303 (2013): 72.
(2) Schmidt, M., et al. Effects of chlorinated acetates on the glutathione metabolism and on glycolysis of cultured astrocytes. Neurotoxicity research 19.4 (2011): 628.
(3) Lu, T.-H., et al. Chloroacetic acid triggers apoptosis in neuronal cells via a reactive oxygen species-induced endoplasmic reticulum stress signaling pathway. Chemico-biological interactions 225 (2015): 1.
(4) Bruschi, S., et al. In vitro cytotoxicity of mono-, di-, and trichloroacetate and its modulation by hepatic peroxisome proliferation. Fundamental and Applied Toxicology 21.3 (1993): 366. |
| | Pathway 1A & Pathway 1B | |
| MIE → KE1
Increased ROS generation → oxidative stress
| (1) Sun, F., et al. Environmental neurotoxic chemicals-induced ubiquitin proteasome system dysfunction in the pathogenesis and progression of Parkinson’s disease. Pharmacology & therapeutics 114.3 (2007): 327.
(2) Bender, A., et al. TOM40 mediates mitochondrial dysfunction induced by α-synuclein accumulation in Parkinson’s disease. PloS one 8.4 (2013): e62277.
(3) Hauser, D.N., et al. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism. Neurobiology of disease 51 (2013): 35.
(4) Mikhed, Y., et al. Mitochondrial oxidative stress, mitochondrial DNA damage and their role in age-related vascular dysfunction. International journal of molecular sciences 16.7 (2015): 15918.
(5) Zhang, W., et al. Mediating effect of ROS on mtDNA damage and low ATP content induced by arsenic trioxide in mouse oocytes. Toxicology in Vitro 25.4 (2011): 979. |
| | Pathway 1A | |
| KE1 → KE2
Oxidative stress causes mtDNA damage | (1) Bender, A., et al. TOM40 mediates mitochondrial dysfunction induced by α-synuclein accumulation in Parkinson’s disease. PloS one 8.4 (2013): e62277.
(2) Mikhed, Y., et al. Mitochondrial oxidative stress, mitochondrial DNA damage and their role in age-related vascular dysfunction. International journal of molecular sciences 16.7 (2015): 15918.
(3) Zhang, W., et al. Mediating effect of ROS on mtDNA damage and low ATP content induced by arsenic trioxide in mouse oocytes. Toxicology in Vitro 25.4 (2011): 979.
(4) Ayala-Peña, S. Role of oxidative DNA damage in mitochondrial dysfunction and Huntington’s disease pathogenesis. Free Radical Biology and Medicine 62 (2013): 102.
(5) Birch‐Machin, M.A., et al. Mitochondrial DNA damage as a biomarker for ultraviolet radiation exposure and oxidative stress. British Journal of Dermatology 169.s2 (2013): 9.
(6) Santos, R.X., et al. Mitochondrial DNA oxidative damage and repair in aging and Alzheimer’s disease. Antioxidants & redox signaling 18.18 (2013): 2444.
(7) Yue, R., et al. Mitochondrial DNA oxidative damage contributes to cardiomyocyte ischemia/reperfusion‐injury in rats: cardioprotective role of lycopene. Journal of cellular physiology 230.9 (2015): 2128.
(8) Han, Y., et al. Oxidative stress induces mitochondrial DNA damage and cytotoxicity through independent mechanisms in human cancer cells. BioMed research international 2013 (2013).
(9) Chan, S.W., et al. Simultaneous quantification of mitochondrial DNA damage and copy number in circulating blood: a sensitive approach to systemic oxidative stress. BioMed research international 2013 (2013).
(10) Wei, Y.-H. Mitochondrial DNA mutations and oxidative damage in aging and diseases: an emerging paradigm of gerontology and medicine. Proceedings of the National Science Council, Republic of China. Part B, Life sciences 22.2 (1998): 55.
(11) Kim, Y.J., et al. Cytoplasmic ribosomal protein S3 (rpS3) plays a pivotal role in mitochondrial DNA damage surveillance. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1833.12 (2013): 2943.
(12) Basu, S., et al. Transcriptional mutagenesis by 8-oxodG in α-synuclein aggregation and the pathogenesis of Parkinson’s disease. Experimental & molecular medicine 47.8 (2015): e179. |
| KE2→ KE3
mtDNA damage causes depolarization of mitochondrial membrane | (1) Kim, S.J., et al. The role of mitochondrial DNA in mediating alveolar epithelial cell apoptosis and pulmonary fibrosis. International journal of molecular sciences 16.9 (2015): 21486.
(2) Santos, J.H., et al. Cell sorting experiments link persistent mitochondrial DNA damage with loss of mitochondrial membrane potential and apoptotic cell death. Journal of biological chemistry 278.3 (2003): 1728.
(3) Ehlers, R.A., et al. Mitochondrial DNA damage and altered membrane potential (ΔΨ) in pancreatic acinar cells induced by reactive oxygen species. Surgery 126.2 (1999): 148. |
| KE3→KE4
Depolarization of mitochondrial membrane → opening of mPTP | (1) Bernardi, P. Modulation of the mitochondrial cyclosporin A-sensitive permeability transition pore by the proton electrochemical gradient. Evidence that the pore can be opened by membrane depolarization. Journal of Biological Chemistry 267.13 (1992): 8834.
(2) Bernardi, P. Modulation of the mitochondrial cyclosporin A-sensitive permeability transition pore by the proton electrochemical gradient. Evidence that the pore can be opened by membrane depolarization. Journal of Biological Chemistry 267.13 (1992): 8834.
(3) Petronilli, V., et al. Modulation of the mitochondrial cyclosporin A-sensitive permeability transition pore. II. The minimal requirements for pore induction underscore a key role for transmembrane electrical potential, matrix pH, and matrix Ca2+. Journal of Biological Chemistry 268.2 (1993): 1011.
(4) Ly, J.D., et al. The mitochondrial membrane potential (Δψm) in apoptosis; an update. Apoptosis 8.2 (2003): 115.
(5) Scorrano, L., et al. On the voltage dependence of the mitochondrial permeability transition pore A critical appraisal. Journal of Biological Chemistry 272.19 (1997): 12295.
(6) Petronilli, V., et al. The voltage sensor of the mitochondrial permeability transition pore is tuned by the oxidation-reduction state of vicinal thiols. Increase of the gating potential by oxidants and its reversal by reducing agents. Journal of Biological Chemistry 269.24 (1994): 16638. |
| KE4→KE5
Opening of mPTP → cytochrome c release | (1) Yang, B.-C., et al. Crotonaldehyde induces apoptosis in alveolar macrophages through intracellular calcium, mitochondria and p53 signaling pathways. The Journal of toxicological sciences 38.2 (2013): 225.
(2) Yamamoto, T., et al. The mechanisms of the release of cytochrome C from mitochondria revealed by proteomics analysis. Yakugaku zasshi: Journal of the Pharmaceutical Society of Japan 132.10 (2012): 1099.
(3) Tornero, D., et al. The role of the mitochondrial permeability transition pore in neurodegenerative processes. Revista de neurologia 35.4 (2002): 354.
(4) Song, T., et al. Protection effect of atorvastatin in cerebral ischemia-reperfusion injury rats by blocking the mitochondrial permeability transition pore. Genet Mol Res 13.4 (2014): 10632.
(5) Ma, X.D., et al. Mechanism of opening of mitochondrial permeability transition pore induced by arsenic trioxide. Ai zheng Aizheng Chinese journal of cancer 25.1 (2006): 17.
(6) Crompton, Martin. The mitochondrial permeability transition pore and its role in cell death. Biochemical Journal 341.2 (1999): 233.
(7) Ou, Z., et al. Mitochondrial-dependent mechanisms are involved in angiotensin II-induced apoptosis in dopaminergic neurons. Journal of the renin-angiotensin-aldosterone system 17.4 (2016): 1470320316672349.
(8) Raza, H., et al. Acetylsalicylic acid-induced oxidative stress, cell cycle arrest, apoptosis and mitochondrial dysfunction in human hepatoma HepG2 cells. European journal of pharmacology 668.1-2 (2011): 15. |
| KE5→KE6
Cytochrome c release → activation of caspases
| (1) Maria, D.A., et al. A novel proteasome inhibitor acting in mitochondrial dysfunction, ER stress and ROS production. Investigational new drugs 31.3 (2013): 493.
(2) Spano, M., et al. The possible involvement of mitochondrial dysfunctions in Lewy body dementia: a systematic review. Functional neurology 30.3 (2015): 151.
(3) Hashimoto, M., et al. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s diseases. Neuromolecular medicine 4.1-2 (2003): 21.
(4) Kakimura, J.-I., et al. Release and aggregation of cytochrome c and α-synuclein are inhibited by the antiparkinsonian drugs, talipexole and pramipexole. European journal of pharmacology 417.1-2 (2001): 59.
(5) Jiang, X., et al. Cytochrome C-mediated apoptosis. Annual review of biochemistry 73 (2004).
(6) Garcia, M., et al. Mitochondria, motor neurons and aging. Journal of the neurological sciences 330.1 (2013): 18.
(7) Lu, C., et al. Neuroprotective effects of tetramethylpyrazine against dopaminergic neuron injury in a rat model of Parkinson’s disease induced by MPTP. International journal of biological sciences 10.4 (2014): 350.
(8) Raza, H., et al. Acetylsalicylic acid-induced oxidative stress, cell cycle arrest, apoptosis and mitochondrial dysfunction in human hepatoma HepG2 cells. European journal of pharmacology 668.1-2 (2011): 15. |
| KE6→ KE7
Caspase activation causes apoptosis | (1) Hernandez-Baltazar, D., et al. Activation of GSK-3β and caspase-3 occurs in nigral dopamine neurons during the development of apoptosis activated by a striatal injection of 6-hydroxydopamine. PloS one 8.8 (2013): e70951.
(2) Li, F., et al. Dysregulated expression of secretogranin III is involved in neurotoxin‐induced dopaminergic neuron apoptosis. Journal of neuroscience research 90.12 (2012): 2237.
(3) Mei, J.-M., et al. Effects of CDNF on 6-OHDA-induced apoptosis in PC12 cells via modulation of Bcl-2/Bax and caspase-3 activation. Neurological Sciences 35.8 (2014): 1275.
(4) Li, D.-W., et al. Guanosine exerts neuroprotective effects by reversing mitochondrial dysfunction in a cellular model of Parkinson’s disease. International journal of molecular medicine 34.5 (2014): 1358.
(5) Naoi, M., et al. Glutathione redox status in mitochondria and cytoplasm differentially and sequentially activates apoptosis cascade in dopamine-melanin-treated SH-SY5Y cells. Neuroscience letters 465.2 (2009): 118. |
| | Pathway 1B | |
| KE1 → KE8
Oxidative stress causes UPS dysfunction | (1) Launay, N., et al. Oxidative stress regulates the ubiquitin–proteasome system and immunoproteasome functioning in a mouse model of X-adrenoleukodystrophy. Brain 136.3 (2013): 891.
(2) Sun, F., et al. Environmental neurotoxic chemicals-induced ubiquitin proteasome system dysfunction in the pathogenesis and progression of Parkinson’s disease. Pharmacology & therapeutics 114.3 (2007): 327.
(3) Chondrogianni, N., et al. Protein damage, repair and proteolysis. Molecular aspects of medicine 35 (2014): 1.
(4) Bendotti, C., et al. Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: implication for protein aggregation and immune response. Progress in neurobiology 97.2 (2012): 101.
(5) Hauser, D.N., et al. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism. Neurobiology of disease 51 (2013): 35.
(6) Dias, V., et al. The role of oxidative stress in Parkinson’s disease. Journal of Parkinson’s disease 3.4 (2013): 461. |
| KE8→ KE9
UPS dysfunction causes protein aggregation | (1) Bendotti, C., et al. Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: implication for protein aggregation and immune response. Progress in neurobiology 97.2 (2012): 101.
(2) Ebrahimi-Fakhari, D., et al. Protein degradation pathways in Parkinson’s disease: curse or blessing. Acta neuropathologica 124.2 (2012): 153.
(3) Riederer, B.M., et al. The role of the ubiquitin proteasome system in Alzheimer’s disease. Experimental Biology and Medicine 236.3 (2011): 268.
(4) Wu, J., et al. Effects of titanium dioxide nanoparticles on α-synuclein aggregation and the ubiquitin-proteasome system in dopaminergic neurons. Artificial cells, nanomedicine, and biotechnology 44.2 (2016): 690.
(5) Chu, Y., et al. Alterations in lysosomal and proteasomal markers in Parkinson’s disease: relationship to alpha-synuclein inclusions. Neurobiology of disease 35.3 (2009): 385.
(6) Sass, M.B., et al. A pragmatic approach to biochemical systems theory applied to an α-synuclein-based model of Parkinson’s disease. Journal of neuroscience methods 178.2 (2009): 366.
(7) Sun, F., et al. Environmental neurotoxic chemicals-induced ubiquitin proteasome system dysfunction in the pathogenesis and progression of Parkinson’s disease. Pharmacology & therapeutics 114.3 (2007): 327. |
| KE9→ KE3
Protein aggregation causes mitochondrial membrane depolarization | (1) Li, L., et al. Human A53T α-synuclein causes reversible deficits in mitochondrial function and dynamics in primary mouse cortical neurons. PLoS One 8.12 (2013): e85815.
(2) Chen, M., et al. Age-dependent alpha-synuclein accumulation is correlated with elevation of mitochondrial TRPC3 in the brains of monkeys and mice. Journal of Neural Transmission 124.4 (2017): 441.
(3) Luth, E.S., et al. Soluble, prefibrillar α-synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction. Journal of Biological Chemistry 289.31 (2014): 21490.
(4) Sarafian, T.A., et al. Impairment of mitochondria in adult mouse brain overexpressing predominantly full-length, N-terminally acetylated human α-synuclein. PloS one 8.5 (2013): e63557.
(5) He, Q., et al. Alpha-synuclein aggregation is involved in the toxicity induced by ferric iron to SK-N-SH neuroblastoma cells. Journal of neural transmission 118.3 (2011): 397.
(6) Ebrahim, A.S., et al. Reduced expression of peroxisome-proliferator activated receptor gamma coactivator-1α enhances α-synuclein oligomerization and down regulates AKT/GSK3β signaling pathway in human neuronal cells that inducibly express α-synuclein. Neuroscience letters 473.2 (2010): 120.
(7) Cleeter, M.W.J., et al. Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage. Neurochemistry international 62.1 (2013): 1. |
| | Pathway 2 | |
| MIE → KE10
Increased ROS causes glutathione depletion | (1) Mailloux, R., et al. Unearthing the secrets of mitochondrial ROS and glutathione in bioenergetics. Trends in biochemical sciences 38.12 (2013): 592.
(2) Ross, E.K., et al. Immunocal® and preservation of glutathione as a novel neuroprotective strategy for degenerative disorders of the nervous system. Recent patents on CNS drug discovery 7.3 (2012): 230.
(3) Meyer, A.J. The integration of glutathione homeostasis and redox signaling. Journal of plant physiology 165.13 (2008): 1390.
(4) Hadi, T., et al. Glutathione prevents preterm parturition and fetal death by targeting macrophage-induced reactive oxygen species production in the myometrium. The FASEB Journal 29.6 (2015): 2653.
(5) You, B.R., et al. Reactive oxygen species, glutathione, and thioredoxin influence suberoyl bishydroxamic acid-induced apoptosis in A549 lung cancer cells. Tumor Biology 36.5 (2015): 3429.
(6) Timme-Laragy, A.R., et al. Glutathione redox dynamics and expression of glutathione-related genes in the developing embryo. Free Radical Biology and Medicine 65 (2013): 89.
(7) You, B.R., et al. Gallic acid-induced lung cancer cell death is accompanied by ROS increase and glutathione depletion. Molecular and cellular biochemistry 357.1-2 (2011): 295.
(8) Dunning, S., et al. Glutathione and antioxidant enzymes serve complementary roles in protecting activated hepatic stellate cells against hydrogen peroxide-induced cell death. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1832.12 (2013): 2027.
(9) You, B.R., et al. Arsenic trioxide induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion. Oncology reports 28.2 (2012): 749.
(10) Quintana-Cabrera, R., et al. Glutathione and γ-glutamylcysteine in the antioxidant and survival functions of mitochondria. (2013): 106.
(11) Thushara, R.M., et al. Sesamol induces apoptosis in human platelets via reactive oxygen species-mediated mitochondrial damage. Biochimie 95.11 (2013): 2060. |
| | Pathway 2A | |
| KE10 → KE1
Glutathione depletion causes oxidative stress | (1) Vaziri, N.D., et al. Induction of oxidative stress by glutathione depletion causes severe hypertension in normal rats. Hypertension 36.1 (2000): 142.
(2) Schulz, J.B., et al. Glutathione, oxidative stress and neurodegeneration. The FEBS Journal 267.16 (2000): 4904.
(3) Shang, Y., et al. Downregulation of glutathione biosynthesis contributes to oxidative stress and liver dysfunction in acute kidney injury. Oxidative medicine and cellular longevity 2016 (2016).
(4) Trocino, R.A., et al. Significance of glutathione depletion and oxidative stress in early embryogenesis in glucose-induced rat embryo culture. Diabetes 44.8 (1995): 992.
(5) Zlatković, J., et al. Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: a histopathological study. European Journal of Pharmaceutical Sciences 59 (2014): 20.
(6) Iguchi, Y., et al. Oxidative stress induced by glutathione depletion reproduces pathological modifications of TDP-43 linked to TDP-43 proteinopathies. Neurobiology of disease 45.3 (2012): 862.
(7) Jung, C.L., et al. Synergistic activation of the Nrf2-signaling pathway by glyceollins under oxidative stress induced by glutathione depletion. Journal of agricultural and food chemistry 61.17 (2013): 4072.
(8) Won, S.J., et al. Assessment at the single-cell level identifies neuronal glutathione depletion as both a cause and effect of ischemia-reperfusion oxidative stress. Journal of Neuroscience 35.18 (2015): 7143.
(9) De Vos, C.H.R., et al. Glutathione depletion due to copper-induced phytochelatin synthesis causes oxidative stress in Silene cucubalus. Plant physiology 98.3 (1992): 853. |
| | Pathway 2B | |
| KE10 →KE11
Glutathione depletion → Calcium dysregulation | (1) Övey, I.S., et al. Homocysteine and cytosolic GSH depletion induce apoptosis and oxidative toxicity through cytosolic calcium overload in the hippocampus of aged mice: involvement of TRPM2 and TRPV1 channels. Neuroscience 284 (2015): 225.
(2) Frosali, S., et al. Role of intracellular calcium and S-glutathionylation in cell death induced by a mixture of isothiazolinones in HL60 cells. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1793.3 (2009): 572.
(3) Orihuela, D., et al. Aluminium-induced impairment of transcellular calcium absorption in the small intestine: calcium uptake and glutathione influence. Journal of inorganic biochemistry 99.9 (2005): 1879.
(4) Macho, A., et al. Glutathione depletion is an early and calcium elevation is a late event of thymocyte apoptosis. The Journal of Immunology 158.10 (1997): 4612.
(5) Grewal, K.K., et al. Bromobenzene and furosemide hepatotoxicity: alterations in glutathione, protein thiols, and calcium. Canadian journal of physiology and pharmacology 74.3 (1996): 257.
(6) Singh, B.K., et al. Nimesulide aggravates redox imbalance and calcium dependent mitochondrial permeability transition leading to dysfunction in vitro. Toxicology 275.1-3 (2010): 1.
(7) Vendemiale, G., et al. Effect of acetaminophen administration on hepatic glutathione compartmentation and mitochondrial energy metabolism in the rat. Biochemical pharmacology 52.8 (1996): 1147.
(8) Marchionatti, A.M., et al. Mitochondrial dysfunction is responsible for the intestinal calcium absorption inhibition induced by menadione. Biochimica et Biophysica Acta (BBA)-General Subjects 1780.2 (2008): 101.
(9) Özgül, C., et al. TRPM2 channel protective properties of N-acetylcysteine on cytosolic glutathione depletion dependent oxidative stress and Ca2+ influx in rat dorsal root ganglion. Physiology & behavior 106.2 (2012): 122.
(10) Yang, B.-C., et al. Crotonaldehyde induces apoptosis in alveolar macrophages through intracellular calcium, mitochondria and p53 signaling pathways. The Journal of toxicological sciences 38.2 (2013): 225.
(11) Övey, I.S., et al. Homocysteine and cytosolic GSH depletion induce apoptosis and oxidative toxicity through cytosolic calcium overload in the hippocampus of aged mice: involvement of TRPM2 and TRPV1 channels. Neuroscience 284 (2015): 225.
(12) Thushara, R.M., et al. Sesamol induces apoptosis in human platelets via reactive oxygen species-mediated mitochondrial damage. Biochimie 95.11 (2013): 2060.
(13) Nazıroğlu, M., et al. Neuroprotection induced by N-acetylcysteine against cytosolic glutathione depletion-induced Ca2+ influx in dorsal root ganglion neurons of mice: role of TRPV1 channels. Neuroscience 242 (2013): 151. |
| KE11→ KE4
Calcium dysregulation causes opening of mPTP | (1) Lu, C., et al. Role of calcium and cyclophilin D in the regulation of mitochondrial permeabilization induced by glutathione depletion. Biochemical and biophysical research communications 363.3 (2007): 572.
(2) Baumgartner, H.K., et al. Calcium elevation in mitochondria is the main Ca2+ requirement for mitochondrial permeability transition pore (mPTP) opening. Journal of Biological Chemistry 284.31 (2009): 20796.
(3) Thushara, R.M., et al. Sesamol induces apoptosis in human platelets via reactive oxygen species-mediated mitochondrial damage. Biochimie 95.11 (2013): 2060.
(4) Zhang, S., et al. Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer letters 208.2 (2004): 143.
(5) Bernardi, P. Mitochondria in muscle cell death. The Italian Journal of Neurological Sciences 20.6 (1999): 395.
(6) Yang, B.-C., et al. Crotonaldehyde induces apoptosis in alveolar macrophages through intracellular calcium, mitochondria and p53 signaling pathways. The Journal of toxicological sciences 38.2 (2013): 225.
(7) Berson, A., et al. The anti-inflammatory drug, nimesulide (4-nitro-2-phenoxymethane-sulfoanilide), uncouples mitochondria and induces mitochondrial permeability transition in human hepatoma cells: protection by albumin. Journal of Pharmacology and Experimental Therapeutics 318.1 (2006): 444.
(8) Lee, G.-H., et al. Bax inhibitor-1-mediated inhibition of mitochondrial Ca 2+ intake regulates mitochondrial permeability transition pore opening and cell death. Scientific reports 4 (2014): 5194.
(9) Barsukova, A., et al. Activation of the mitochondrial permeability transition pore modulates Ca2+ responses to physiological stimuli in adult neurons. European Journal of Neuroscience 33.5 (2011): 831.
(10) Moon, S.H., et al. Genetic ablation of calcium-independent phospholipase A2γ (iPLA2γ) attenuates calcium-induced opening of the mitochondrial permeability transition pore and resultant cytochrome c release. Journal of Biological Chemistry 287.35 (2012): 29837.
(11) Yamamoto, T., et al. The mechanisms of the release of cytochrome C from mitochondria revealed by proteomics analysis. Yakugaku zasshi: Journal of the Pharmaceutical Society of Japan 132.10 (2012): 1099.
(12) Rasola, A., et al. The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis 12.5 (2007): 815.
(13) De la Fuente, S., et al. The Spatial Distribution of the Na+/Ca2+ Exchanger in Cardiac Mitochondria Enhances the Efficincy of the Mitochondrial Ca2+ Signal Generation. Biophysical Journal 114.3 (2018): 659a.
(14) Kannurpatti, S.S., et al. Calcium sequestering ability of mitochondria modulates influx of calcium through glutamate receptor channel. Neurochemical research 25.12 (2000): 1527.
(15) Rueda, C.B., et al. Glutamate excitotoxicity and Ca2+-regulation of respiration: Role of the Ca2+ activated mitochondrial transporters (CaMCs). Biochimica et Biophysica Acta (BBA)-Bioenergetics 1857.8 (2016): 1158.
(16) Baines, C.P., et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434.7033 (2005): 658.
(17) Basso, E., et al. Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. Journal of Biological Chemistry 280.19 (2005): 18558. |
| | Pathway 2C | |
| KE10→ KE12
Glutathione depletion causes ATP depletion | (1) Almeida, A., et al. Glutamate neurotoxicity is associated with nitric oxide-mediated mitochondrial dysfunction and glutathione depletion. Brain research 790.1-2 (1998): 209.
(2) Vesce, S., et al. Acute glutathione depletion restricts mitochondrial ATP export in cerebellar granule neurons. Journal of Biological Chemistry 280.46 (2005): 38720.
(3) Schütt, F., et al. Moderately reduced ATP levels promote oxidative stress and debilitate autophagic and phagocytic capacities in human RPE cells. Investigative ophthalmology & visual science 53.9 (2012): 5354.
(4) Huang, J., et al. Cellular responses of cultured cerebellar astrocytes to ethacrynic acid-induced perturbation of subcellular glutathione homeostasis. Brain research 711.1-2 (1996): 184.
(5) Zeevalk, G.D., et al. Energy Stress‐Induced Dopamine Loss in Glutathione Peroxidase‐Overexpressing Transgenic Mice and in Glutathione‐Depleted Mesencephalic Cultures. Journal of neurochemistry 68.1 (1997): 426.
(6) Den Boer, P.J., et al. Effect of glutathione depletion on the cytotoxicity of xenobiotics and induction of single-strand DNA breaks by ionizing radiation in isolated hamster round spermatids. Journal of reproduction and fertility 88.1 (1990): 259.
(7) Vesce, S., et al. Acute glutathione depletion restricts mitochondrial ATP export in cerebellar granule neurons. Journal of Biological Chemistry 280.46 (2005): 38720.
(8) Navarini, A.L.F., et al. Hydroxychalcones induce apoptosis in B16-F10 melanoma cells via GSH and ATP depletion. European journal of medicinal chemistry 44.4 (2009): 1630.
(9) Locatelli, C., et al. Gallic acid ester derivatives induce apoptosis and cell adhesion inhibition in melanoma cells: the relationship between free radical generation, glutathione depletion and cell death. Chemico-biological interactions 181.2 (2009): 175.
(10) Raza, H., et al. Acetylsalicylic acid-induced oxidative stress, cell cycle arrest, apoptosis and mitochondrial dysfunction in human hepatoma HepG2 cells. European journal of pharmacology 668.1-2 (2011): 15.
(11) Mithöfer, K., et al. Mitochondrial poisons cause depletion of reduced glutathione in isolated hepatocytes. Archives of biochemistry and biophysics 295.1 (1992): 132. |
| KE12→ KE11
ATP depletion causes calcium dysregulation | (1) Bruce, J.I.E. Plasma membrane calcium pump regulation by metabolic stress. World journal of biological chemistry 1.7 (2010): 221.
(2) Spivey, J.R., et al. Glycochenodeoxycholate-induced lethal hepatocellular injury in rat hepatocytes. Role of ATP depletion and cytosolic free calcium. The Journal of clinical investigation 92.1 (1993): 17.
(3) Akopova, O.V., et al. The effect of ATP-dependent K (+)-channel opener on the functional state and the opening of cyclosporine-sensitive pore in rat liver mitochondria. Ukrains’ kyi biokhimichnyi zhurnal (1999) 85.3 (2013): 38.
(4) Zhang, R., et al. Involvement of calcium, reactive oxygen species, and ATP in hexavalent chromium-induced damage in red blood cells. Cellular Physiology and Biochemistry 34.5 (2014): 1780.
(5) James, A.D., et al. Glycolytic ATP fuels the plasma membrane calcium pump critical for pancreatic cancer cell survival. Journal of Biological Chemistry 288.50 (2013): 36007.
(6) James, A.D., et al. The plasma membrane calcium pump in pancreatic cancer cells exhibiting the Warburg effect relies on glycolytic ATP. Journal of Biological Chemistry 290.41 (2015): 24760.
(7) Cejka, J.-C., et al. Activation of calcium influx by ATP and store depletion in primary cultures of renal proximal cells. Pflügers Archiv 427.1-2 (1994): 33.
(8) Chao, C.‐C., et al. Ca2+ store depletion and endoplasmic reticulum stress are involved in P2X7 receptor‐mediated neurotoxicity in differentiated NG108‐15 cells. Journal of cellular biochemistry 113.4 (2012): 1377.
(9) Mattson, M.P., et al. Energetics and oxidative stress in synaptic plasticity and neurodegenerative disorders. Neuromolecular medicine 2.2 (2002): 215.
(10) Bernardi, P. Mitochondria in muscle cell death. The Italian Journal of Neurological Sciences 20.6 (1999): 395.
(11) Berson, A., et al. The anti-inflammatory drug, nimesulide (4-nitro-2-phenoxymethane-sulfoanilide), uncouples mitochondria and induces mitochondrial permeability transition in human hepatoma cells: protection by albumin. Journal of Pharmacology and Experimental Therapeutics 318.1 (2006): 444. |
| | Adverse Outcomes | |
| KE7→ AO1
Apoptosis causes mitochondrial disease | (1) Du, Ya., et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proceedings of the National Academy of Sciences 98.25 (2001): 14669.
(2) Chung, K.K.K., et al. New insights into Parkinson’s disease. Journal of neurology 250.3 (2003): iii15.
(3) Thomas, K.J., et al. The role of PTEN-induced kinase 1 in mitochondrial dysfunction and dynamics. The international journal of biochemistry & cell biology 41.10 (2009): 2025.
(4) Nordström, U., et al. Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson’s disease. Neurobiology of disease 73 (2015): 70.
(5) Van der Perren, A., et al. Longitudinal follow-up and characterization of a robust rat model for Parkinson’s disease based on overexpression of alpha-synuclein with adeno-associated viral vectors. Neurobiology of aging 36.3 (2015): 1543.
(6) Ares-Santos, S., et al. Methamphetamine causes degeneration of dopamine cell bodies and terminals of the nigrostriatal pathway evidenced by silver staining. Neuropsychopharmacology 39.5 (2014): 1066.
(7) Gantz, S.C., et al. Loss of Mecp2 in substantia nigra dopamine neurons compromises the nigrostriatal pathway. Journal of Neuroscience 31.35 (2011): 12629.
(8) Panayotis, N., et al. Morphological and functional alterations in the substantia nigra pars compacta of the Mecp2-null mouse. Neurobiology of disease 41.2 (2011): 385.
(9) Matsuura, K., et al. Cyclosporin A attenuates degeneration of dopaminergic neurons induced by 6-hydroxydopamine in the mouse brain. Brain research 733.1 (1996): 101.
(10) Walters, T.L., et al. Diethyldithiocarbamate causes nigral cell loss and dopamine depletion with nontoxic doses of MPTP. Experimental neurology 156.1 (1999): 62.
(11) Raza, H., et al. Acetylsalicylic acid-induced oxidative stress, cell cycle arrest, apoptosis and mitochondrial dysfunction in human hepatoma HepG2 cells. European journal of pharmacology 668.1-2 (2011): 15. |
| AO1 → AO2
Mitochondrial disease causes symptoms of organ system failure | (1) Crouser, E.D. Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion 4.5 (2004): 729.
(2) Ares-Santos, S., et al. Methamphetamine causes degeneration of dopamine cell bodies and terminals of the nigrostriatal pathway evidenced by silver staining. Neuropsychopharmacology 39.5 (2014): 1066.
(3) Colebrooke, R.E., et al. Age‐related decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson’s disease. European Journal of Neuroscience 24.9 (2006): 2622.
(4) Panayotis, N., et al. Morphological and functional alterations in the substantia nigra pars compacta of the Mecp2-null mouse. Neurobiology of disease 41.2 (2011): 385.
(5) Willard, A.M., et al. Differential degradation of motor deficits during gradual dopamine depletion with 6-hydroxydopamine in mice. Neuroscience 301 (2015): 254.
(6) Heuer, A., et al. Dopamine-rich grafts alleviate deficits in contralateral response space induced by extensive dopamine depletion in rats. Experimental neurology 247 (2013): 485.
(7) Plowman, E.K., et al. Differential sensitivity of cranial and limb motor function to nigrostriatal dopamine depletion. Behavioural brain research 237 (2013): 157.
(8) Plowman, E.K., et al. Striatal dopamine depletion induces forelimb motor impairments and disrupts forelimb movement representations within the motor cortex. Journal of Parkinson’s disease 1.1 (2011): 93.
(9) Christopher, L., et al. Combined insular and striatal dopamine dysfunction are associated with executive deficits in Parkinson’s disease with mild cognitive impairment. Brain 137.2 (2013): 565.
(10) Plowman, E.K., et al. Behavioral and neurophysiological correlates of striatal dopamine depletion: A rodent model of Parkinson’s disease. Journal of communication disorders 44.5 (2011): 549.
(11) Charlton, C.G., et al. Striatal dopamine depletion, tremors, and hypokinesia following the intracranial injection of S-adenosylmethionine. Molecular and chemical neuropathology 26.3 (1995): 269. |
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