Soluble Uric Acid Activates the NLRP3 Inflammasome

Scientific Reports

Volumn 7, Issue , 2017, Pages

  Braga, Tarcio Teodoro ^a,b   Forni, Maria Fernanda ^a   Correa Costa, Matheus ^a   Ramos, Rodrigo Nalio ^a   Barbuto, Jose Alexandre ^a   Branco, Paola ^a   Castoldi, Angela ^a   Hiyane, Meire Ioshie ^a   Davanso, Mariana Rodrigues ^b   Latz, Eicke ^b,c,d,e   Franklin, Bernardo S ^b   Kowaltowski, Alicia J ^a   Camara, Niels Olsen Saraiva ^a,f  

^a UNIVERSITY OF SÃO PAULO   (Brazil)

^b UNIVERSITY HOSPITAL BONN   (Germany)

^c UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

^d GERMAN CENTER FOR NEURODEGENERATIVE DISEASES DZNE   (Germany)

^e NORWEGIAN UNIVERSITY OF SCIENCE AND TECHNOLOGY   (Norway)

^f FEDERAL UNIVERSITY OF SÃO PAULO   (Brazil)

Author keywords

[No Author keywords available]

Indexed keywords

CRYOPYRIN; INFLAMMASOME; INTERLEUKIN 1BETA; INTERLEUKIN 1BETA CONVERTING ENZYME; MYELOID DIFFERENTIATION FACTOR 88; REACTIVE OXYGEN METABOLITE; URIC ACID; VOLTAGE DEPENDENT ANION CHANNEL;

ANIMAL; C57BL MOUSE; CELL CULTURE; DISEASE MODEL; FIBROSIS; GENETICS; KIDNEY; KIDNEY DISEASE; KNOCKOUT MOUSE; MACROPHAGE; MALE; METABOLISM; MOUSE; OXIDATION REDUCTION REACTION; PATHOLOGY; PHYSIOLOGY;

ANIMALS; CASPASE 1; CELLS, CULTURED; DISEASE MODELS, ANIMAL; FIBROSIS; INFLAMMASOMES; INTERLEUKIN-1BETA; KIDNEY; KIDNEY DISEASES; MACROPHAGES; MALE; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; MYELOID DIFFERENTIATION FACTOR 88; NLR FAMILY, PYRIN DOMAIN-CONTAINING 3 PROTEIN; OXIDATION-REDUCTION; REACTIVE OXYGEN SPECIES; URIC ACID; VOLTAGE-DEPENDENT ANION CHANNELS;

EID: 85009502184     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep39884     Document Type: Article

References (102)

1. So, A. & Thorens, B. Uric acid transport and disease. Journal of Clinical Investigation 120, 1791-1799, doi: 10.1172/jci42344 (2010).
2. Patschan, D., Patschan, S., Gobe, G. G., Chintala, S. & Goligorsky, M. S. Uric acid heralds ischemic tissue injury to mobilize endothelial progenitor cells. Journal of the American Society of Nephrology 18, 1516-1524, doi: 10.1681/asn.2006070759 (2007).
3. Shi, Y., Evans, J. E. & Rock, K. L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516-521, doi: 10.1038/nature01991 (2003).
4. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237-241, doi: 10.1038/nature04516 (2006).
5. Di Giovine, F. S., Malawista, S. E., Nuki, G. & Duff, G. W. Interleukin 1 (IL 1) as a mediator of crystal arthritis. Stimulation of T cell and synovial fibroblast mitogenesis by urate crystal-induced IL 1. J Immunol 138, 3213-3218 (1987).
6. Martinon, F., Burns, K. & Tschopp, J. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Molecular cell 10, 417-426 (2002).
7. Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature immunology 9, 847-856, doi: 10.1038/ni.1631 (2008).
8. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357-1361, doi: 10.1038/nature08938 (2010).
9. Dostert, C. et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674-677, doi: 10.1126/science.1156995 (2008).
10. Franklin, B. S., Mangan, M. S. & Latz, E. Crystal Formation in Inflammation. Annual review of immunology 34, 173-202, doi: 10.1146/annurev-immunol-041015-055539 (2016).
11. Lima, H. Jr. et al. Role of lysosome rupture in controlling Nlrp3 signaling and necrotic cell death. Cell Cycle 12, 1868-1878, doi: 10.4161/cc.24903 (2013).
12. Schaefer, L. Complexity of danger: The diverse nature of damage-associated molecular patterns. The Journal of biological chemistry 289, 35237-35245, doi: 10.1074/jbc.R114.619304 (2014).
13. Crisan, T. O. et al. Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra. Annals of the rheumatic diseases 75, 755-762, doi: 10.1136/annrheumdis-2014-206564 (2016).
14. Acauan Filho, B. J. et al. Serum nitrate and NOx levels in preeclampsia are higher than in normal pregnancy. Hypertension in pregnancy 35, 226-233, doi: 10.3109/10641955.2016.1139718 (2016).
15. Johnson, R. J., Lanaspa, M. A. & Gaucher, E. A. Uric acid: A danger signal from the RNA world that may have a role in the epidemic of obesity, metabolic syndrome, and cardiorenal disease: evolutionary considerations. Seminars in nephrology 31, 394-399, doi: 10.1016/j.semnephrol.2011.08.002 (2011).
16. Cicerchi, C. et al. Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 28, 3339-3350, doi: 10.1096/fj.13-243634 (2014).
17. Kratzer, J. T. et al. Evolutionary history and metabolic insights of ancient mammalian uricases. Proceedings of the National Academy of Sciences of the United States of America 111, 3763-3768, doi: 10.1073/pnas.1320393111 (2014).
18. Madero, M. et al. Uric Acid and Long-term Outcomes in CKD. American Journal of Kidney Diseases 53, 796-803, doi: 10.1053/j. ajkd.2008.12.021 (2009).
19. Suliman, M. E. et al. J-shaped mortality relationship for uric acid in CKD. American Journal of Kidney Diseases 48, 761-771, doi: 10.1053/j.ajkd.2006.08.019 (2006).
20. Gasse, P. et al. Uric Acid Is a Danger Signal Activating NALP3 Inflammasome in Lung Injury Inflammation and Fibrosis. American Journal of Respiratory and Critical Care Medicine 179, 903-913, doi: 10.1164/rccm.200808-1274OC (2009).
21. Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annual review of immunology 27, 229-265, doi: 10.1146/annurev.immunol.021908.132715 (2009).
22. Choi, J. S. & Ryter, S. W. Inflammasomes: Molecular Regulation and Implications for Metabolic and Cognitive Diseases. Molecules and cells, doi: 10.14348/molcells.2014.0104 (2014).
23. Martinon, F. & Tschopp, J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117, 561-574, doi: 10.1016/j.cell.2004.05.004 (2004).
24. Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A. & Kolodner, R. D. Mutation of a new gene encoding a putative pyrinlike protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nature genetics 29, 301-305, doi: 10.1038/ng756 (2001).
25. Agostini, L. et al. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20, 319-325 (2004).
26. Coll, R. C. et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature medicine 21, 248-255, doi: 10.1038/nm.3806 (2015).
27. Youm, Y. H. et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nature medicine 21, 263-269, doi: 10.1038/nm.3804 (2015).
28. Abderrazak, A. et al. NLRP3 inflammasome: from a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases. Redox biology 4, 296-307, doi: 10.1016/j.redox.2015.01.008 (2015).
29. Gurung, P., Lukens, J. R. & Kanneganti, T. D. Mitochondria: diversity in the regulation of the NLRP3 inflammasome. Trends in molecular medicine 21, 193-201, doi: 10.1016/j.molmed.2014.11.008 (2015).
30. Garaude, J. et al. Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense. Nature immunology, doi: 10.1038/ni.3509 (2016).
31. Freeman, L. C. & Ting, J. P. The pathogenic role of the inflammasome in neurodegenerative diseases. Journal of neurochemistry 136 Suppl 1, 29-38, doi: 10.1111/jnc.13217 (2016).
32. Heneka, M. T., Kummer, M. P. & Latz, E. Innate immune activation in neurodegenerative disease. Nature reviews. Immunology 14, 463-477, doi: 10.1038/nri3705 (2014).
33. Eisenbarth, S. C., Colegio, O. R., O'Connor, W., Sutterwala, F. S. & Flavell, R. A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122-1126, doi: 10.1038/nature06939 (2008).
34. Franklin, B. S., Mangan, M. S. & Latz, E. Crystal Formation in Inflammation. Annual review of immunology, doi: 10.1146/annurevimmunol-041015-055539 (2016).
35. Ganeshan, K. & Chawla, A. Metabolic regulation of immune responses. Annual review of immunology 32, 609-634, doi: 10.1146/annurev-immunol-032713-120236 (2014).
36. Figueira, T. R. et al. Mitochondria as a source of reactive oxygen and nitrogen species: from molecular mechanisms to human health. Antioxidants & redox signaling 18, 2029-2074, doi: 10.1089/ars.2012.4729 (2013).
37. Quinlan, C. L., Perevoshchikova, I. V., Hey-Mogensen, M., Orr, A. L. & Brand, M. D. Sites of reactive oxygen species generation by mitochondria oxidizing different substrates. Redox biology 1, 304-312, doi: 10.1016/j.redox.2013.04.005 (2013).
38. Sena, L. A. & Chandel, N. S. Physiological roles of mitochondrial reactive oxygen species. Molecular cell 48, 158-167, doi: 10.1016/j. molcel.2012.09.025 (2012).
39. Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401-414, doi: 10.1016/j.immuni.2012.01.009 (2012).
40. Iyer, S. S. et al. Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity 39, 311-323, doi: 10.1016/j. immuni.2013.08.001 (2013).
41. Murakami, T. et al. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proceedings of the National Academy of Sciences of the United States of America 109, 11282-11287, doi: 10.1073/pnas.1117765109 (2012).
42. Weinberg, S. E., Sena, L. A. & Chandel, N. S. Mitochondria in the regulation of innate and adaptive immunity. Immunity 42, 406-417, doi: 10.1016/j.immuni.2015.02.002 (2015).
43. Engerson, T. D. et al. Conversion of xanthine dehydrogenase to oxidase in ischemic rat-tissues. Journal of Clinical Investigation 79, 1564-1570, doi: 10.1172/jci112990 (1987).
44. Lukens, J. R. et al. The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells. Immunity 42, 654-664, doi: 10.1016/j.immuni.2015.03.006 (2015).
45. Cui, J. et al. NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4. Nature immunology 13, 387-395, doi: 10.1038/ni.2239 (2012).
46. Kono, H., Chen, C. J., Ontiveros, F. & Rock, K. L. Uric acid promotes an acute inflammatory response to sterile cell death in mice. The Journal of clinical investigation 120, 1939-1949, doi: 10.1172/JCI40124 (2010).
47. Hooper, D. C. et al. Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America 95, 675-680 (1998).
48. Braga, T. T. et al. MyD88 signaling pathway is involved in renal fibrosis by favoring a TH2 immune response and activating alternative M2 macrophages. Mol Med 18, 1231-1239, doi: 10.2119/molmed.2012.00131 (2012).
49. Plank, M. S., Calderon, T. C., Asmerom, Y., Boskovic, D. S. & Angeles, D. M. Biochemical measurement of neonatal hypoxia. Journal of visualized experiments: JoVE, doi: 10.3791/2948 (2011).
50. Martin, A. C. & Brown, M. A. Could uric acid have a pathogenic role in pre-eclampsiaNature reviews. Nephrology 6, 744-748, doi: 10.1038/nrneph.2010.125 (2010).
51. Klahr, S. & Morrissey, J. Obstructive nephropathy and renal fibrosis. American journal of physiology. Renal physiology 283, F861-875, doi: 10.1152/ajprenal.00362.2001 (2002).
52. Dendooven, A. et al. Oxidative stress in obstructive nephropathy. International journal of experimental pathology 92, 202-210, doi: 10.1111/j.1365-2613.2010.00730.x (2011).
53. Julian, D., April, K. L., Patel, S., Stein, J. R. & Wohlgemuth, S. E. Mitochondrial depolarization following hydrogen sulfide exposure in erythrocytes from a sulfide-tolerant marine invertebrate. The Journal of experimental biology 208, 4109-4122, doi: 10.1242/jeb.01867 (2005).
54. Pastore, A., Federici, G., Bertini, E. & Piemonte, F. Analysis of glutathione: implication in redox and detoxification. Clinica chimica acta; international journal of clinical chemistry 333, 19-39 (2003).
55. Zheng, Q. et al. Reactive oxygen species activated NLRP3 inflammasomes initiate inflammation in hyperosmolarity stressed human corneal epithelial cells and environment-induced dry eye patients. Experimental eye research 134, 133-140, doi: 10.1016/j. exer.2015.02.013 (2015).
56. Jabir, M. S. et al. Mitochondrial damage contributes to Pseudomonas aeruginosa activation of the inflammasome and is downregulated by autophagy. Autophagy 11, 166-182, doi: 10.4161/15548627.2014.981915 (2015).
57. Liu, D. et al. Activation of the Nlrp3 inflammasome by mitochondrial reactive oxygen species: A novel mechanism of albumininduced tubulointerstitial inflammation. The international journal of biochemistry & cell biology 57, 7-19, doi: 10.1016/j. biocel.2014.09.018 (2014).
58. Lupfer, C. & Kanneganti, T. D. Unsolved Mysteries in NLR Biology. Frontiers in immunology 4, 285, doi: 10.3389/fimmu.2013.00285 (2013).
59. Gross, O., Thomas, C. J., Guarda, G. & Tschopp, J. The inflammasome: An integrated view. Immunological reviews 243, 136-151, doi: 10.1111/j.1600-065X.2011.01046.x (2011).
60. Forni, M. F., Chausse, B., Peloggia, J. & Kowaltowski, A. J. Bioenergetic profiling in the skin. Experimental dermatology 25, 147-148, doi: 10.1111/exd.12856 (2016).
61. Kevei, E. & Hoppe, T. Ubiquitin sets the timer: impacts on aging and longevity. Nature structural & molecular biology 21, 290-292, doi: 10.1038/nsmb.2806 (2014).
62. Segref, A. et al. Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system. Cell metabolism 19, 642-652, doi: 10.1016/j.cmet.2014.01.016 (2014).
63. Infantino, V., Iacobazzi, V., Menga, A., Avantaggiati, M. L. & Palmieri, F. A key role of the mitochondrial citrate carrier (SLC25A1) in TNFalpha-and IFNgamma-triggered inflammation. Biochimica et biophysica acta 1839, 1217-1225, doi: 10.1016/j. bbagrm.2014.07.013 (2014).
64. Lanaspa, M. A. et al. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructosedependent and-independent fatty liver. The Journal of biological chemistry 287, 40732-40744, doi: 10.1074/jbc.M112.399899 (2012).
65. Wang, W. et al. Mitofusin-2 triggers mitochondria Ca2+ influx from the endoplasmic reticulum to induce apoptosis in hepatocellular carcinoma cells. Cancer letters 358, 47-58, doi: 10.1016/j.canlet.2014.12.025 (2015).
66. de Brito, O. M. & Scorrano, L. Mitofusin 2: A mitochondria-shaping protein with signaling roles beyond fusion. Antioxidants & redox signaling 10, 621-633, doi: 10.1089/ars.2007.1934 (2008).
67. Debattisti, V., Pendin, D., Ziviani, E., Daga, A. & Scorrano, L. Reduction of endoplasmic reticulum stress attenuates the defects caused by Drosophila mitofusin depletion. The Journal of cell biology 204, 303-312, doi: 10.1083/jcb.201306121 (2014).
68. Huang, H. et al. An interaction between Bcl-xL and the voltage-dependent anion channel (VDAC) promotes mitochondrial Ca2+ uptake. The Journal of biological chemistry 288, 19870-19881, doi: 10.1074/jbc.M112.448290 (2013).
69. Gatliff, J. et al. TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control. Autophagy 10, 2279-2296, doi: 10.4161/15548627.2014.991665 (2014).
70. Gatliff, J. & Campanella, M. TSPO is a REDOX regulator of cell mitophagy. Biochemical Society transactions 43, 543-552, doi: 10.1042/BST20150037 (2015).
71. Gatliff, J. & Campanella, M. TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria. The Biochemical journal 473, 107-121, doi: 10.1042/BJ20150899 (2016).
72. Messina, A., Reina, S., Guarino, F. & De Pinto, V. VDAC isoforms in mammals. Biochimica et biophysica acta 1818, 1466-1476, doi: 10.1016/j.bbamem.2011.10.005 (2012).
73. Huang, H., Shah, K., Bradbury, N. A., Li, C. & White, C. Mcl-1 promotes lung cancer cell migration by directly interacting with VDAC to increase mitochondrial Ca2+ uptake and reactive oxygen species generation. Cell death & disease 5, e1482, doi: 10.1038/cddis.2014.419 (2014).
74. Wolf, A. J. et al. Hexokinase Is an Innate Immune Receptor for the Detection of Bacterial Peptidoglycan. Cell, doi: 10.1016/j. cell.2016.05.076 (2016).
75. Johnson, R. J., Andrews, P., Benner, S. A. & Oliver, W. Theodore E. Woodward award. The evolution of obesity: insights from the mid-Miocene. Transactions of the American Clinical and Climatological Association 121, 295-305, discussion 305-298 (2010).
76. Glantzounis, G. K., Tsimoyiannis, E. C., Kappas, A. M. & Galaris, D. A. Uric acid and oxidative stress. Current pharmaceutical design 11, 4145-4151 (2005).
77. Stocker, R. & Keaney, J. F. Jr. Role of oxidative modifications in atherosclerosis. Physiological reviews 84, 1381-1478, doi: 10.1152/physrev.00047.2003 (2004).
78. Johnson, R. J. et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal diseaseHypertension 41, 1183-1190, doi: 10.1161/01.HYP.0000069700.62727.C5 (2003).
79. Furukawa, S. et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. The Journal of clinical investigation 114, 1752-1761, doi: 10.1172/JCI21625 (2004).
80. Wellen, K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. The Journal of clinical investigation 115, 1111-1119, doi: 10.1172/JCI25102 (2005).
81. Sautin, Y. Y., Nakagawa, T., Zharikov, S. & Johnson, R. J. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. American journal of physiology. Cell physiology 293, C584-596, doi: 10.1152/ajpcell.00600.2006 (2007).
82. Gaudry, M. et al. Crystal-induced neutrophil activation. III. Inflammatory microcrystals induce a distinct pattern of tyrosine phosphorylation in human neutrophils. The Journal of clinical investigation 91, 1649-1655, doi: 10.1172/JCI116373 (1993).
83. Dai, H. et al. Combined Association of Serum Uric Acid and Metabolic Syndrome with Chronic Kidney Disease in Hypertensive Patients. Kidney & blood pressure research 41, 413-423, doi: 10.1159/000443443 (2016).
84. Bascands, J. L. & Schanstra, J. P. Obstructive nephropathy: Insights from genetically engineered animals. Kidney International 68, 925-937, doi: 10.1111/j.1523-1755.2005.00486.x (2005).
85. Pulskens, W. P. et al. TLR4 Promotes Fibrosis but Attenuates Tubular Damage in Progressive Renal Injury. Journal of the American Society of Nephrology 21, 1299-1308, doi: 10.1681/asn.2009070722 (2010).
86. Leemans, J. C. et al. The Role of Toll-Like Receptor 2 in Inflammation and Fibrosis during Progressive Renal Injury. Plos One 4, doi: e5704 10.1371/journal.pone.0005704 (2009).
87. Xin, B.-m. et al. Activation of Toll-like receptor 9 attenuates unilateral ureteral obstruction-induced renal fibrosis. Acta Pharmacologica Sinica 31, 1583-1592, doi: 10.1038/aps.2010.202 (2010).
88. Paredes-Juarez, G. A. et al. DAMP production by human islets under low oxygen and nutrients in the presence or absence of an immunoisolating-capsule and necrostatin-1. Scientific reports 5, 14623, doi: 10.1038/srep14623 (2015).
89. Beharrie, A. et al. A functional immature model of chronic partial ureteral obstruction. Kidney international 65, 1155-1161, doi: 10.1111/j.1523-1755.2004.00488.x (2004).
90. Liu, C. F. et al. Rapamycin reduces renal hypoxia, interstitial inflammation and fibrosis in a rat model of unilateral ureteral obstruction. Clinical and investigative medicine. Medecine clinique et experimentale 37, E142 (2014).
91. Ludwig-Portugall, I. et al. An NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice. Kidney international, doi: 10.1016/j.kint.2016.03.035 (2016).
92. Anders, H. J. & Schaefer, L. Beyond tissue injury-damage-associated molecular patterns, toll-like receptors, and inflammasomes also drive regeneration and fibrosis. Journal of the American Society of Nephrology: JASN 25, 1387-1400, doi: 10.1681/ASN.2014010117 (2014).
93. Cruz, C. M. et al. ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. The Journal of biological chemistry 282, 2871-2879, doi: 10.1074/jbc.M608083200 (2007).
94. Yang, Y. et al. Effect of uric acid on mitochondrial function and oxidative stress in hepatocytes. Genetics and molecular research: GMR 15, doi: 10.4238/gmr.15028644 (2016).
95. Dranka, B. P., Hill, B. G. & Darley-Usmar, V. M. Mitochondrial reserve capacity in endothelial cells: The impact of nitric oxide and reactive oxygen species. Free radical biology & medicine 48, 905-914, doi: 10.1016/j.freeradbiomed.2010.01.015 (2010).
96. Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221-225, doi: 10.1038/nature09663 (2011).
97. da-Silva, W. S. et al. Mitochondrial bound hexokinase activity as a preventive antioxidant defense: steady-state ADP formation as a regulatory mechanism of membrane potential and reactive oxygen species generation in mitochondria. The Journal of biological chemistry 279, 39846-39855, doi: 10.1074/jbc.M403835200 (2004).
98. Stutz, A., Horvath, G. L., Monks, B. G. & Latz, E. ASC speck formation as a readout for inflammasome activation. Methods Mol Biol 1040, 91-101, doi: 10.1007/978-1-62703-523-1-8 (2013).
99. Imamura, R. et al. Erythropoietin protects the kidneys against ischemia reperfusion injury by activating hypoxia inducible factor-1 alpha. Transplantation 83, 1371-1379, doi: 10.1097/01.tp.0000264200.38926.70 (2007).
100. Reddy, G. K. & Enwemeka, C. S. A simplified method for the analysis of hydroxyproline in biological tissues. Clinical biochemistry 29, 225-229 (1996).
101. Rahman, I., Kode, A. & Biswas, S. K. Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nature protocols 1, 3159-3165, doi: 10.1038/nprot.2006.378 (2006).
102. Wu, M. et al. Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. American journal of physiology. Cell physiology 292, C125-136, doi: 10.1152/ajpcell.00247.2006 (2007).