References

1. Miller, S.I.; Ernst, R.K.; Bader, M.W. LPS, TLR4 and infectious disease diversity. Nat. Rev. Microbiol. 2005, 3, 36–46.
2. Nikolaeva, S.; Bachteeva, V.; Fock, E.; Herterich, S.; Lavrova, E.; Borodkina, A.; Gambaryan, S.; Parnova, R. Frog urinary bladder epithelial cells express TLR4 and respond to bacterial LPS by increase of iNOS expression and L-arginine uptake. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2012, 303, R1042–R1052.
3. Lien, E.; Ingalls, R.R. Toll-like receptors. Crit. Care Med. 2002, 30, S1–S11.
4. Lu, Y.C.; Yeh, W.C.; Ohashi, P.S. LPS/TLR4 signal transduction pathway. Cytokine 2008, 42, 145–151.
5. Takeda, K.; Akira, S. TLR signaling pathways. Semin. Immunol. 2004, 16, 3–9.
6. Mazgaeen, L.; Gurung, P. Recent Advances in Lipopolysaccharide Recognition Systems. Int. J. Mol. Sci 2020, 21, 379.
7. Tschopp, J. Mitochondria: Sovereign of inflammation? Eur. J. Immunol. 2011, 41, 1196–1202.
8. Evavold, C.L.; Kagan, J.C. How Inflammasomes Inform Adaptive Immunity. J. Mol. Biol. 2018, 430, 217–237.
9. Dagenais, M.; Skeldon, A.; Saleh, M. The inflammasome: In memory of Dr. Jurg Tschopp. Cell Death Differ. 2012, 19, 5–12.
10. Demirel, I.; Persson, A.; Brauner, A.; Sarndahl, E.; Kruse, R.; Persson, K. Activation of the NLRP3 Inflammasome Pathway by Uropathogenic Escherichia coli Is Virulence Factor-Dependent and Influences Colonization of Bladder Epithelial Cells. Front. Cell Infect. Microbiol. 2018, 8, 81.
11. Swanson, K.V.; Deng, M.; Ting, J.P. The NLRP3 inflammasome: Molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 2019, 19, 477–489.
12. Liu, X.; Zhang, Z.; Ruan, J.; Pan, Y.; Magupalli, V.G.; Wu, H.; Lieberman, J. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 2016, 535, 153–158.
13. Murphy, M.P. How mitochondria produce reactive oxygen species. Biochem. J. 2009, 417, 1–13.
14. Skulachev, V.P. Cationic antioxidants as a powerful tool against mitochondrial oxidative stress. Biochem. Biophys. Res. Commun. 2013, 441, 275–279.
15. Sies, H.; Berndt, C.; Jones, D.P. Oxidative Stress. Annu. Rev. Biochem. 2017, 86, 715–748.
16. Andreyev, A.Y.; Kushnareva, Y.E.; Murphy, A.N.; Starkov, A.A. Mitochondrial ROS Metabolism: 10 Years Later. Biochemistry (Moscow) 2015, 80, 517–531.
17. Robb, E.L.; Hall, A.R.; Prime, T.A.; Eaton, S.; Szibor, M.; Viscomi, C.; James, A.M.; Murphy, M.P. Control of mitochondrial superoxide production by reverse electron transport at complex I. J. Biol. Chem. 2018, 293, 9869–9879.
18. Treberg, J.R.; Quinlan, C.L.; Brand, M.D. Evidence for two sites of superoxide production by mitochondrial NADH-ubiquinone oxidoreductase (complex I). J. Biol. Chem. 2011, 286, 27103–27110.
19. Hirst, J.; King, M.S.; Pryde, K.R. The production of reactive oxygen species by complex I. Biochem. Soc. Trans. 2008, 36, 976–980.
20. Zhang, S.; Zhou, Q.; Li, Y.; Zhang, Y.; Wu, Y. MitoQ Modulates Lipopolysaccharide-Induced Intestinal Barrier Dysfunction via Regulating Nrf2 Signaling. Mediat. Inflamm. 2020, 2020, 3276148.
21. Bellezza, I.; Giambanco, I.; Minelli, A.; Donato, R. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim. Biophys. Acta Mol. Cell Res. 2018, 1865, 721–733.
22. Zorov, D.B.; Bannikova, S.Y.; Belousov, V.V.; Vyssokikh, M.Y.; Zorova, L.D.; Isaev, N.K.; Krasnikov, B.F.; Plotnikov, E.Y. Reactive oxygen and nitrogen species: Friends or foes? Biochemistry (Moscow) 2005, 70, 215–221.
23. Droge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 2002, 82, 47–95.
24. Kozlov, A.V.; Bahrami, S.; Calzia, E.; Dungel, P.; Gille, L.; Kuznetsov, A.V.; Troppmair, J. Mitochondrial dysfunction and biogenesis: Do ICU patients die from mitochondrial failure? Ann. Intensive Care 2011, 1, 41.
25. Zorov, D.B.; Juhaszova, M.; Sollott, S.J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol. Rev. 2014, 94, 909–950.
26. Prauchner, C.A. Oxidative stress in sepsis: Pathophysiological implications justifying antioxidant co-therapy. Burns 2017, 43, 471–485.
27. Di Meo, S.; Reed, T.; Venditti, P.; Victor, V. Role of ROS and RNS sources in physiological and pathological conditions. Oxidative Med. Cell Longev. 2016, 2016, 1245049.
28. Yang, Y.; Karakhanova, S.; Hartwig, W.; D’Haese, J.G.; Philippov, P.P.; Werner, J.; Bazhin, A.V. Mitochondria and Mitochondrial ROS in Cancer: Novel Targets for Anticancer Therapy. J. Cell. Physiol. 2016, 231, 2570–2581.
29. Robinson, A.R.; Yousefzadeh, M.J.; Rozgaja, T.A.; Wang, J.; Li, X.; Tilstra, J.S.; Feldman, C.H.; Gregg, S.Q.; Johnson, C.H.; Skoda, E.M.; et al. Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. Redox Biol. 2018, 17, 259–273.
30. Zhang, D.; Li, Y.; Heims-Waldron, D.; Bezzerides, V.; Guatimosim, S.; Guo, Y.; Gu, F.; Zhou, P.; Lin, Z.; Ma, Q.; et al. Mitochondrial Cardiomyopathy Caused by Elevated Reactive Oxygen Species and Impaired Cardiomyocyte Proliferation. Circ. Res. 2018, 122, 74–87.
31. De, I.; Dogra, N.; Singh, S. The Mitochondrial Unfolded Protein Response: Role in Cellular Homeostasis and Disease. Curr. Mol. Med. 2017, 17, 587–597.
32. Yao, X.; Carlson, D.; Sun, Y.; Ma, L.; Wolf, S.E.; Minei, J.P.; Zang, Q.S. Mitochondrial ROS Induces Cardiac Inflammation via a Pathway through mtDNA Damage in a Pneumonia-Related Sepsis Model. PLoS ONE 2015, 10, e0139416.
33. Callahan, L.A.; Supinski, G.S. Sepsis induces diaphragm electron transport chain dysfunction and protein depletion. Am. J. Respir. Crit. Care Med. 2005, 172, 861–868.
34. Paradies, G.; Petrosillo, G.; Paradies, V.; Ruggiero, F.M. Role of cardiolipin peroxidation and Ca2+ in mitochondrial dysfunction and disease. Cell Calcium. 2009, 45, 643–650.
35. Orrenius, S.; Gogvadze, V.; Zhivotovsky, B. Calcium and mitochondria in the regulation of cell death. Biochem. Biophys. Res. Commun. 2015, 460, 72–81.
36. Williamson, J.; Davison, G. Targeted Antioxidants in Exercise-Induced Mitochondrial Oxidative Stress: Emphasis on DNA Damage. Antioxidants (Basel) 2020, 9, 142.
37. Galley, H.F. Oxidative stress and mitochondrial dysfunction in sepsis. Br. J. Anaesth. 2011, 107, 57–64.
38. Poderoso, J.J. The formation of peroxynitrite in the applied physiology of mitochondrial nitric oxide. Arch. Biochem. Biophys. 2009, 484, 214–220.
39. Rocha, M.; Herance, R.; Rovira, S.; Hernandez-Mijares, A.; Victor, V.M. Mitochondrial dysfunction and antioxidant therapy in sepsis. Infect. Disord. Drug Targets 2012, 12, 161–178.
40. Supinski, G.S.; Schroder, E.A.; Callahan, L.A. Mitochondria and Critical Illness. Chest 2020, 157, 310–322.
41. Voloboueva, L.A.; Emery, J.F.; Sun, X.; Giffard, R.G. Inflammatory response of microglial BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose-regulated protein 75/mortalin. FEBS Lett. 2013, 587, 756–762.
42. Park, J.; Min, J.S.; Kim, B.; Chae, U.B.; Yun, J.W.; Choi, M.S.; Kong, I.K.; Chang, K.T.; Lee, D.S. Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-kappaB pathways. Neurosci. Lett. 2015, 584, 191–196.
43. Supinski, G.S.; Wang, L.; Schroder, E.A.; Callahan, L.A.P. MitoTEMPOL, a mitochondrial targeted antioxidant, prevents sepsis-induced diaphragm dysfunction. Am. J. Physiol. Lung Cell Mol. Physiol. 2020, 319, L228–L238.
44. Li, X.; Wang, X.; Zheng, M.; Luan, Q.X. Mitochondrial reactive oxygen species mediate the lipopolysaccharide-induced pro-inflammatory response in human gingival fibroblasts. Exp. Cell Res. 2016, 347, 212–221.
45. Jiao, P.; Li, W.; Shen, L.; Li, Y.; Yu, L.; Liu, Z. The protective effect of doxofylline against lipopolysaccharides (LPS)-induced activation of NLRP3 inflammasome is mediated by SIRT1 in human pulmonary bronchial epithelial cells. Artif. Cells Nanomed. Biotechnol. 2020, 48, 687–694.
46. Mills, E.L.; Kelly, B.; Logan, A.; Costa, A.S.; Varma, M.; Bryant, C.E.; Tourlomousis, P.; Däbritz, J.H.M.; Gottlieb, E.; Latorre, I. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 2016, 167, 457–470.e413.
47. Zhang, J.; Wang, L.; Xie, W.; Hu, S.; Zhou, H.; Zhu, P.; Zhu, H. Melatonin attenuates ER stress and mitochondrial damage in septic cardiomyopathy: A new mechanism involving BAP31 upregulation and MAPK-ERK pathway. J. Cell. Physiol. 2020, 235, 2847–2856.
48. Lowes, D.A.; Almawash, A.M.; Webster, N.R.; Reid, V.L.; Galley, H.F. Melatonin and structurally similar compounds have differing effects on inflammation and mitochondrial function in endothelial cells under conditions mimicking sepsis. Br. J. Anaesth. 2011, 107, 193–201.
49. Ding, Z.; Wu, X.; Wang, Y.; Ji, S.; Zhang, W.; Kang, J.; Li, J.; Fei, G. Melatonin prevents LPS-induced epithelial-mesenchymal transition in human alveolar epithelial cells via the GSK-3beta/Nrf2 pathway. Biomed. Pharmacother. 2020, 132, 110827.
50. Liu, Y.; Yang, W.; Sun, X.; Xie, L.; Yang, Y.; Sang, M.; Jiao, R. SS31 Ameliorates Sepsis-Induced Heart Injury by Inhibiting Oxidative Stress and Inflammation. Inflammation 2019, 42, 2170–2180.
51. Sener, G.; Toklu, H.; Kapucu, C.; Ercan, F.; Erkanli, G.; Kacmaz, A.; Tilki, M.; Yegen, B.C. Melatonin protects against oxidative organ injury in a rat model of sepsis. Surg. Today 2005, 35, 52–59.
52. Vanasco, V.; Magnani, N.D.; Cimolai, M.C.; Valdez, L.B.; Evelson, P.; Boveris, A.; Alvarez, S. Endotoxemia impairs heart mitochondrial function by decreasing electron transfer, ATP synthesis and ATP content without affecting membrane potential. J. Bioenerg. Biomembr. 2012, 44, 243–252.
53. Patil, N.K.; Parajuli, N.; MacMillan-Crow, L.A.; Mayeux, P.R. Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: Mitochondria-targeted antioxidant mitigates injury. Am. J. Physiol. Renal. Physiol. 2014, 306, F734–F743.
54. Chandel, N.S.; McClintock, D.S.; Feliciano, C.E.; Wood, T.M.; Melendez, J.A.; Rodriguez, A.M.; Schumacker, P.T. Reactive oxygen species generated at mitochondrial Complex III stabilize HIF-1-alpha during hypoxia: A mechanism of O2 sensing. J. Biol. Chem. 2000, 275, 25130–25138.
55. Quoilin, C.; Mouithys-Mickalad, A.; Duranteau, J.; Gallez, B.; Hoebeke, M. Endotoxin-induced basal respiration alterations of renal HK-2 cells: A sign of pathologic metabolism down-regulation. Biochem. Biophys. Res. Commun. 2012, 423, 350–354.
56. Fock, E.; Bachteeva, V.; Lavrova, E.; Parnova, R. Mitochondrial-Targeted Antioxidant MitoQ Prevents E. coli Lipopolysaccharide-Induced Accumulation of Triacylglycerol and Lipid Droplets Biogenesis in Epithelial Cells. J. Lipids 2018, 2018, 5745790.
57. Jeger, V.; Brandt, S.; Porta, F.; Jakob, S.M.; Takala, J.; Djafarzadeh, S. Dose response of endotoxin on hepatocyte and muscle mitochondrial respiration in vitro. Biomed. Res. Int. 2015, 2015, 353074.
58. Karlsson, M.; Hara, N.; Morata, S.; Sjovall, F.; Kilbaugh, T.; Hansson, M.J.; Uchino, H.; Elmer, E. Diverse and Tissue-Specific Mitochondrial Respiratory Response in a Mouse Model of Sepsis-Induced Multiple Organ Failure. Shock 2016, 45, 404–410.
59. Frisard, M.I.; Wu, Y.; McMillan, R.P.; Voelker, K.A.; Wahlberg, K.A.; Anderson, A.S.; Boutagy, N.; Resendes, K.; Ravussin, E.; Hulver, M.W. Low levels of lipopolysaccharide modulate mitochondrial oxygen consumption in skeletal muscle. Metabolism 2015, 64, 416–427.
60. Apostolova, N.; Garcia-Bou, R.; Hernandez-Mijares, A.; Herance, R.; Rocha, M.; Victor, V.M. Mitochondrial antioxidants alleviate oxidative and nitrosative stress in a cellular model of sepsis. Pharm. Res. 2011, 28, 2910–2919.
61. Qiu, Z.; He, Y.; Ming, H.; Lei, S.; Leng, Y.; Xia, Z.Y. Lipopolysaccharide (LPS) Aggravates High Glucose- and Hypoxia/Reoxygenation-Induced Injury through Activating ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis in H9C2 Cardiomyocytes. J. Diabetes Res. 2019, 2019, 8151836.
62. Zhang, H.; Zhang, W.; Jiao, F.; Li, X.; Zhang, H.; Wang, L.; Gong, Z. The nephroprotective effect of MS-275 on lipopolysaccharide (LPS)-induced acute kidney injury by inhibiting reactive oxygen species (ROS)-oxidative stress and endoplasmic reticulum stress. Med. Sci. Mon. Int. Med. J. Exp. Clin. Res. 2018, 24, 2620.
63. Raulien, N.; Friedrich, K.; Strobel, S.; Rubner, S.; Baumann, S.; von Bergen, M.; Korner, A.; Krueger, M.; Rossol, M.; Wagner, U. Fatty Acid Oxidation Compensates for Lipopolysaccharide-Induced Warburg Effect in Glucose-Deprived Monocytes. Front. Immunol. 2017, 8, 609.
64. Palsson-McDermott, E.M.; Curtis, A.M.; Goel, G.; Lauterbach, M.A.; Sheedy, F.J.; Gleeson, L.E.; van den Bosch, M.W.; Quinn, S.R.; Domingo-Fernandez, R.; Johnston, D.G. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab. 2015, 21, 65–80.
65. Kelly, B.; Tannahill, G.M.; Murphy, M.P.; O’Neill, L.A. Metformin Inhibits the Production of Reactive Oxygen Species from NADH:Ubiquinone Oxidoreductase to Limit Induction of Interleukin-1β (IL-1β) and Boosts Interleukin-10 (IL-10) in Lipopolysaccharide (LPS)-activated Macrophages. J. Biol. Chem. 2015, 290, 20348–20359.
66. West, A.P.; Brodsky, I.E.; Rahner, C.; Woo, D.K.; Erdjument-Bromage, H.; Tempst, P.; Walsh, M.C.; Choi, Y.; Shadel, G.S.; Ghosh, S. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 2011, 472, 476–480.
67. Kopp, E.; Medzhitov, R.; Carothers, J.; Xiao, C.; Douglas, I.; Janeway, C.A.; Ghosh, S. ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes Dev. 1999, 13, 2059–2071.
68. Geng, J.; Sun, X.; Wang, P.; Zhang, S.; Wang, X.; Wu, H.; Hong, L.; Xie, C.; Li, X.; Zhao, H.; et al. Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. Nat. Immunol. 2015, 16, 1142–1152.
69. Tur, J.; Pereira-Lopes, S.; Vico, T.; Marin, E.A.; Munoz, J.P.; Hernandez-Alvarez, M.; Cardona, P.J.; Zorzano, A.; Lloberas, J.; Celada, A. Mitofusin 2 in Macrophages Links Mitochondrial ROS Production, Cytokine Release, Phagocytosis, Autophagy, and Bactericidal Activity. Cell Rep. 2020, 32, 108079.
70. Williams, R.J.; Spencer, J.P.; Rice-Evans, C. Flavonoids: Antioxidants or signalling molecules? Free Radic. Biol. Med. 2004, 36, 838–849.
71. Murphy, M.P. Antioxidants as therapies: Can we improve on nature? Free Radical. Biol. Med. 2014, 66, 20–23.
72. Haddad, J.J.; Land, S.C. Redox/ROS regulation of lipopolysaccharide-induced mitogen-activated protein kinase (MAPK) activation and MAPK-mediated TNF-alpha biosynthesis. Br. J. Pharmacol. 2002, 135, 520–536.
73. Runkel, E.D.; Liu, S.; Baumeister, R.; Schulze, E. Surveillance-activated defenses block the ROS-induced mitochondrial unfolded protein response. PLoS Genet. 2013, 9, e1003346.
74. Martindale, J.L.; Holbrook, N.J. Cellular response to oxidative stress: Signaling for suicide and survival. J. Cell. Physiol. 2002, 192, 1–15.
75. Chen, L.; Liu, P.; Feng, X.; Ma, C. Salidroside suppressing LPS-induced myocardial injury by inhibiting ROS-mediated PI3K/Akt/mTOR pathway in vitro and in vivo. J. Cell. Mol. Med. 2017, 21, 3178–3189.
76. Liberman, E.A.; Topaly, V.P. Permeability of bimolecular phospholipid membranes for fat-soluble ions. Biofizika 1969, 14, 452–461.
77. Kelso, G.F.; Porteous, C.M.; Hughes, G.; Ledgerwood, E.C.; Gane, A.M.; Smith, R.A.; Murphy, M.P. Prevention of mitochondrial oxidative damage using targeted antioxidants. Ann. N. Y. Acad. Sci. 2002, 959, 263–274.
78. Battogtokh, G.; Choi, Y.S.; Kang, D.S.; Park, S.J.; Shim, M.S.; Huh, K.M.; Cho, Y.Y.; Lee, J.Y.; Lee, H.S.; Kang, H.C. Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: Current strategies and future perspectives. Acta Pharm. Sin. B 2018, 8, 862–880.
79. Zielonka, J.; Joseph, J.; Sikora, A.; Hardy, M.; Ouari, O.; Vasquez-Vivar, J.; Cheng, G.; Lopez, M.; Kalyanaraman, B. Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications. Chem. Rev. 2017, 117, 10043–10120.
80. Murphy, M.P.; Smith, R.A. Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu. Rev. Pharmacol. Toxicol. 2007, 47, 629–656.
81. Skulachev, M.V.; Antonenko, Y.N.; Anisimov, V.N.; Chernyak, B.V.; Cherepanov, D.A.; Chistyakov, V.A.; Egorov, M.V.; Kolosova, N.G.; Korshunova, G.A.; Lyamzaev, K.G.; et al. Mitochondrial-targeted plastoquinone derivatives. Effect on senescence and acute age-related pathologies. Curr. Drug Targets 2011, 12, 800–826.
82. Trnka, J.; Blaikie, F.H.; Smith, R.A.; Murphy, M.P. A mitochondria-targeted nitroxide is reduced to its hydroxylamine by ubiquinol in mitochondria. Free Radic. Biol. Med. 2008, 44, 1406–1419.
83. Smith, R.A.; Porteous, C.M.; Coulter, C.V.; Murphy, M.P. Selective targeting of an antioxidant to mitochondria. Eur. J. Biochem. 1999, 263, 709–716.
84. James, A.M.; Cocheme, H.M.; Smith, R.A.; Murphy, M.P. Interactions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species. Implications for the use of exogenous ubiquinones as therapies and experimental tools. J. Biol. Chem. 2005, 280, 21295–21312.
85. Fetisova, E.K.; Muntyan, M.S.; Lyamzaev, K.G.; Chernyak, B.V. Therapeutic Effect of the Mitochondria-Targeted Antioxidant SkQ1 on the Culture Model of Multiple Sclerosis. Oxidative Med. Cell. Longev. 2019, 2019, 2082561.
86. Ross, M.F.; Da Ros, T.; Blaikie, F.H.; Prime, T.A.; Porteous, C.M.; Severina, I.I.; Skulachev, V.P.; Kjaergaard, H.G.; Smith, R.A.; Murphy, M.P. Accumulation of lipophilic dications by mitochondria and cells. Biochem. J. 2006, 400, 199–208.
87. Plotnikov, E.Y.; Zorov, D.B. Pros and Cons of Use of Mitochondria-Targeted Antioxidants. Antioxidants 2019, 8, 316.
88. Plotnikov, E.Y.; Morosanova, M.A.; Pevzner, I.B.; Zorova, L.D.; Manskikh, V.N.; Pulkova, N.V.; Galkina, S.I.; Skulachev, V.P.; Zorov, D.B. Protective effect of mitochondria-targeted antioxidants in an acute bacterial infection. Proc. Natl. Acad. Sci. USA 2013, 110, E3100–E3108.
89. Lei, X.; Li, S.; Luo, C.; Wang, Y.; Liu, Y.; Xu, Z.; Huang, Q.; Zou, F.; Chen, Y.; Peng, F.; et al. Micheliolide Attenuates Lipopolysaccharide-Induced Inflammation by Modulating the mROS/NF-kappaB/NLRP3 Axis in Renal Tubular Epithelial Cells. Mediat. Inflamm. 2020, 2020, 3934769.
90. Weidinger, A.; Mullebner, A.; Paier-Pourani, J.; Banerjee, A.; Miller, I.; Lauterbock, L.; Duvigneau, J.C.; Skulachev, V.P.; Redl, H.; Kozlov, A.V. Vicious inducible nitric oxide synthase-mitochondrial reactive oxygen species cycle accelerates inflammatory response and causes liver injury in rats. Antioxid. Redox Signal. 2015, 22, 572–586.
91. Lowes, D.A.; Thottakam, B.M.; Webster, N.R.; Murphy, M.P.; Galley, H.F. The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis. Free Radic. Biol. Med. 2008, 45, 1559–1565.
92. Minter, B.E.; Lowes, D.A.; Webster, N.R.; Galley, H.F. Differential Effects of MitoVitE, alpha-Tocopherol and Trolox on Oxidative Stress, Mitochondrial Function and Inflammatory Signalling Pathways in Endothelial Cells Cultured under Conditions Mimicking Sepsis. Antioxidants 2020, 9, 195.
93. Di, S.; Wang, Z.; Hu, W.; Yan, X.; Ma, Z.; Li, X.; Li, W.; Gao, J. The Protective Effects of Melatonin Against LPS-Induced Septic Myocardial Injury: A Potential Role of AMPK-Mediated Autophagy. Front. Endocrinol. (Lausanne) 2020, 11, 162.
94. Asayama, S.; Kawamura, E.; Nagaoka, S.; Kawakami, H. Design of manganese porphyrin modified with mitochondrial signal peptide for a new antioxidant. Mol. Pharm. 2006, 3, 468–470.
95. Mo, Y.N.; Deng, S.Y.; Zhang, L.N.; Huang, Y.; Li, W.C.; Peng, Q.Y.; Liu, Z.Y.; Ai, Y.H. SS-31 reduces inflammation and oxidative stress through the inhibition of Fis1 expression in lipopolysaccharide-stimulated microglia. Biochem. Biophys. Res. Commun. 2019, 520, 171–178.
96. Fink, M.P.; Macias, C.A.; Xiao, J.; Tyurina, Y.Y.; Delude, R.L.; Greenberger, J.S.; Kagan, V.E.; Wipf, P. Hemigramicidin-TEMPO conjugates: Novel mitochondria-targeted antioxidants. Crit. Care Med. 2007, 35, S461–S467.
97. Xue, Y.; Du, M.; Zhu, M.J. Quercetin suppresses NLRP3 inflammasome activation in epithelial cells triggered by Escherichia coli O157:H7. Free Radic. Biol. Med. 2017, 108, 760–769.
98. Supinski, G.S.; Murphy, M.P.; Callahan, L.A. MitoQ administration prevents endotoxin-induced cardiac dysfunction. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009, 297, R1095–R1102.
99. Plotnikov, E.Y.; Pevzner, I.B.; Zorova, L.D.; Chernikov, V.P.; Prusov, A.N.; Kireev, I.I.; Silachev, D.N.; Skulachev, V.P.; Zorov, D.B. Mitochondrial Damage and Mitochondria-Targeted Antioxidant Protection in LPS-Induced Acute Kidney Injury. Antioxidants 2019, 8, 176.
100. Lowes, D.; Webster, N.; Murphy, M.; Galley, H. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Br. J. Anaesth. 2013, 110, 472–480.
101. Wang, H.; Li, L.; Zhao, M.; Chen, Y.H.; Zhang, Z.H.; Zhang, C.; Ji, Y.L.; Meng, X.H.; Xu, D.X. Melatonin alleviates lipopolysaccharide-induced placental cellular stress response in mice. J. Pineal. Res. 2011, 50, 418–426.
102. Lopez, L.C.; Escames, G.; Tapias, V.; Utrilla, P.; Leon, J.; Acuna-Castroviejo, D. Identification of an inducible nitric oxide synthase in diaphragm mitochondria from septic mice—Its relation with mitochondrial dysfunction and prevention by melatonin. Int. J. Biochem. Cell B 2006, 38, 267–278.
103. Zhao, W.; Xu, Z.; Cao, J.; Fu, Q.; Wu, Y.; Zhang, X.; Long, Y.; Zhang, X.; Yang, Y.; Li, Y.; et al. Elamipretide (SS-31) improves mitochondrial dysfunction, synaptic and memory impairment induced by lipopolysaccharide in mice. J. Neuroinflamm. 2019, 16, 230.
104. Li, G.; Wu, J.; Li, R.; Yuan, D.; Fan, Y.; Yang, J.; Ji, M.; Zhu, S. Protective Effects of Antioxidant Peptide SS-31 Against Multiple Organ Dysfunctions During Endotoxemia. Inflammation 2016, 39, 54–64.
105. Wu, J.; Zhang, M.; Hao, S.; Jia, M.; Ji, M.; Qiu, L.; Sun, X.; Yang, J.; Li, K. Mitochondria-Targeted Peptide Reverses Mitochondrial Dysfunction and Cognitive Deficits in Sepsis-Associated Encephalopathy. Mol. Neurobiol. 2015, 52, 783–791.
106. Macarthur, H.; Couri, D.M.; Wilken, G.H.; Westfall, T.C.; Lechner, A.J.; Matuschak, G.M.; Chen, Z.; Salvemini, D. Modulation of serum cytokine levels by a novel superoxide dismutase mimetic, M40401, in an Escherichia coli model of septic shock: Correlation with preserved circulating catecholamines. Crit. Care Med. 2003, 31, 237–245.
107. Smith, R.A.; Porteous, C.M.; Gane, A.M.; Murphy, M.P. Delivery of bioactive molecules to mitochondria in vivo. Proc. Natl. Acad. Sci. USA 2003, 100, 5407–5412.
108. Huet, O.; Dupic, L.; Harrois, A.; Duranteau, J. Oxidative stress and endothelial dysfunction during sepsis. Front. Biosci. (Landmark Ed.) 2011, 16, 1986–1995.
109. Rademann, P.; Weidinger, A.; Drechsler, S.; Meszaros, A.; Zipperle, J.; Jafarmadar, M.; Dumitrescu, S.; Hacobian, A.; Ungelenk, L.; Rostel, F.; et al. Mitochondria-Targeted Antioxidants SkQ1 and MitoTEMPO Failed to Exert a Long-Term Beneficial Effect in Murine Polymicrobial Sepsis. Oxid. Med. Cell Longev. 2017, 2017, 6412682.
110. Reily, C.; Mitchell, T.; Chacko, B.K.; Benavides, G.; Murphy, M.P.; Darley-Usmar, V. Mitochondrially targeted compounds and their impact on cellular bioenergetics. Redox Biol. 2013, 1, 86–93.
111. Gottwald, E.M.; Duss, M.; Bugarski, M.; Haenni, D.; Schuh, C.D.; Landau, E.M.; Hall, A.M. The targeted anti-oxidant MitoQ causes mitochondrial swelling and depolarization in kidney tissue. Physiol. Rep. 2018, 6, e13667.
112. Patkova, J.; Andel, M.; Trnka, J. Palmitate-induced cell death and mitochondrial respiratory dysfunction in myoblasts are not prevented by mitochondria-targeted antioxidants. Cell Physiol. Biochem. 2014, 33, 1439–1451.
113. Doughan, A.K.; Dikalov, S.I. Mitochondrial redox cycling of mitoquinone leads to superoxide production and cellular apoptosis. Antioxid. Redox Signal. 2007, 9, 1825–1836.
114. James, A.M.; Smith, R.A.; Murphy, M.P. Antioxidant and prooxidant properties of mitochondrial Coenzyme Q. Arch. Biochem. Biophys. 2004, 423, 47–56.
115. Pokrzywinski, K.L.; Biel, T.G.; Kryndushkin, D.; Rao, V.A. Therapeutic Targeting of the Mitochondria Initiates Excessive Superoxide Production and Mitochondrial Depolarization Causing Decreased mtDNA Integrity. PLoS ONE 2016, 11, e0168283.
116. Cheng, G.; Zielonka, J.; McAllister, D.M.; Mackinnon, A.C., Jr.; Joseph, J.; Dwinell, M.B.; Kalyanaraman, B. Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death. BMC Cancer 2013, 13, 285.
117. Smith, R.A.; Murphy, M.P. Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann. N. Y. Acad. Sci. 2010, 1201, 96–103.
118. Fink, B.D.; Herlein, J.A.; Yorek, M.A.; Fenner, A.M.; Kerns, R.J.; Sivitz, W.I. Bioenergetic effects of mitochondrial-targeted coenzyme Q analogs in endothelial cells. J. Pharmacol. Exp. Ther. 2012, 342, 709–719.
119. Lowes, D.A.; Wallace, C.; Murphy, M.P.; Webster, N.R.; Galley, H.F. The mitochondria targeted antioxidant MitoQ protects against fluoroquinolone-induced oxidative stress and mitochondrial membrane damage in human Achilles tendon cells. Free Radic. Res. 2009, 43, 323–328.
120. McManus, M.J.; Murphy, M.P.; Franklin, J.L. Mitochondria-derived reactive oxygen species mediate caspase-dependent and -independent neuronal deaths. Mol. Cell Neurosci. 2014, 63, 13–23.
121. Murphy, M.P.; Hartley, R.C. Mitochondria as a therapeutic target for common pathologies. Nat. Rev. Drug Discov. 2018, 17, 865–886.
122. Socaciu, A.I.; Ionut, R.; Socaciu, M.A.; Ungur, A.P.; Barsan, M.; Chiorean, A.; Socaciu, C.; Rajnoveanu, A.G. Melatonin, an ubiquitous metabolic regulator: Functions, mechanisms and effects on circadian disruption and degenerative diseases. Rev. Endocr. Metab. Disord. 2020, 21, 465–478.
123. Reiter, R.J.; Mayo, J.C.; Tan, D.X.; Sainz, R.M.; Alatorre-Jimenez, M.; Qin, L. Melatonin as an antioxidant: Under promises but over delivers. J. Pineal Res. 2016, 61, 253–278.
124. Colunga Biancatelli, R.M.L.; Berrill, M.; Mohammed, Y.H.; Marik, P.E. Melatonin for the treatment of sepsis: The scientific rationale. J. Thorac. Dis. 2020, 12, S54–S65.
125. Andersen, L.P.; Werner, M.U.; Rosenkilde, M.M.; Fenger, A.Q.; Petersen, M.C.; Rosenberg, J.; Gogenur, I. Pharmacokinetics of high-dose intravenous melatonin in humans. J. Clin. Pharmacol. 2016, 56, 324–329.
126. Posadzki, P.P.; Bajpai, R.; Kyaw, B.M.; Roberts, N.J.; Brzezinski, A.; Christopoulos, G.I.; Divakar, U.; Bajpai, S.; Soljak, M.; Dunleavy, G.; et al. Melatonin and health: An umbrella review of health outcomes and biological mechanisms of action. BMC Med. 2018, 16, 18.
127. Poeggeler, B.; Saarela, S.; Reiter, R.J.; Tan, D.X.; Chen, L.D.; Manchester, L.C.; Barlow-Walden, L.R. Melatonin—A highly potent endogenous radical scavenger and electron donor: New aspects of the oxidation chemistry of this indole accessed in vitro. Ann. N. Y. Acad. Sci. 1994, 738, 419–420.
128. Tan, D.X.; Manchester, L.C.; Reiter, R.J.; Qi, W.B.; Karbownik, M.; Calvo, J.R. Significance of melatonin in antioxidative defense system: Reactions and products. Biol. Sign. Recept 2000, 9, 137–159.
129. Tan, D.X.; Manchester, L.C.; Terron, M.P.; Flores, L.J.; Reiter, R.J. One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species? J. Pineal Res. 2007, 42, 28–42.
130. Venegas, C.; Garcia, J.A.; Escames, G.; Ortiz, F.; Lopez, A.; Doerrier, C.; Garcia-Corzo, L.; Lopez, L.C.; Reiter, R.J.; Acuna-Castroviejo, D. Extrapineal melatonin: Analysis of its subcellular distribution and daily fluctuations. J. Pineal Res. 2012, 52, 217–227.
131. Tan, D.-X.; Manchester, L.C.; Esteban-Zubero, E.; Zhou, Z.; Reiter, R.J. Melatonin as a potent and inducible endogenous antioxidant: Synthesis and metabolism. Molecules 2015, 20, 18886–18906.
132. He, C.; Wang, J.; Zhang, Z.; Yang, M.; Li, Y.; Tian, X.; Ma, T.; Tao, J.; Zhu, K.; Song, Y.; et al. Mitochondria Synthesize Melatonin to Ameliorate Its Function and Improve Mice Oocyte’s Quality under in Vitro Conditions. Int. J. Mol. Sci. 2016, 17, 939.
133. Lopez, A.; Garcia, J.A.; Escames, G.; Venegas, C.; Ortiz, F.; Lopez, L.C.; Acuna-Castroviejo, D. Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production. J. Pineal Res. 2009, 46, 188–198.
134. Paradies, G.; Paradies, V.; Ruggiero, F.M.; Petrosillo, G. Protective role of melatonin in mitochondrial dysfunction and related disorders. Arch. Toxicol. 2015, 89, 923–939.
135. Acuna Castroviejo, D.; Lopez, L.C.; Escames, G.; López, A.; Garcia, J.A.; Reiter, R.J. Melatonin-mitochondria interplay in health and disease. Curr. Top. Med. Chem. 2011, 11, 221–240.
136. Vriend, J.; Reiter, R.J. Melatonin, bone regulation and the ubiquitin-proteasome connection: A review. Life Sci. 2016, 145, 152–160.
137. Janjetovic, Z.; Jarrett, S.G.; Lee, E.F.; Duprey, C.; Reiter, R.J.; Slominski, A.T. Melatonin and its metabolites protect human melanocytes against UVB-induced damage: Involvement of NRF2-mediated pathways. Sci. Rep. 2017, 7, 1–13.
138. Zhai, M.; Li, B.; Duan, W.; Jing, L.; Zhang, B.; Zhang, M.; Yu, L.; Liu, Z.; Yu, B.; Ren, K.; et al. Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis. J. Pineal Res. 2017, 63, e12419.
139. Wu, J.Y.; Tsou, M.Y.; Chen, T.H.; Chen, S.J.; Tsao, C.M.; Wu, C.C. Therapeutic effects of melatonin on peritonitis-induced septic shock with multiple organ dysfunction syndrome in rats. J. Pineal Res. 2008, 45, 106–116.
140. Zhao, K.; Zhao, G.M.; Wu, D.; Soong, Y.; Birk, A.V.; Schiller, P.W.; Szeto, H.H. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J. Biol. Chem. 2004, 279, 34682–34690.
141. Szeto, H.H. Mitochondria-targeted cytoprotective peptides for ischemia-reperfusion injury. Antioxid. Redox Signal. 2008, 10, 601–619.
142. Szeto, H.H. Development of mitochondria-targeted aromatic-cationic peptides for neurodegenerative diseases. Ann. N. Y. Acad. Sci. 2008, 1147, 112–121.
143. Birk, A.V.; Liu, S.; Soong, Y.; Mills, W.; Singh, P.; Warren, J.D.; Seshan, S.V.; Pardee, J.D.; Szeto, H.H. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J. Am. Soc. Nephrol. 2013, 24, 1250–1261.
144. Birk, A.V.; Chao, W.M.; Bracken, C.; Warren, J.D.; Szeto, H.H. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br. J. Pharmacol. 2014, 171, 2017–2028.
145. Iyer, S.S.; He, Q.; Janczy, J.R.; Elliott, E.I.; Zhong, Z.; Olivier, A.K.; Sadler, J.J.; Knepper-Adrian, V.; Han, R.Z.; Qiao, L.; et al. Mitochondrial Cardiolipin Is Required for Nlrp3 Inflammasome Activation. Immunity 2013, 39, 311–323.
146. Birk, A.V.; Chao, W.M.; Liu, S.; Soong, Y.; Szeto, H.H. Disruption of cytochrome c heme coordination is responsible for mitochondrial injury during ischemia. Biochim. Biophys. Acta 2015, 1847, 1075–1084.
147. Szeto, H.H. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br. J. Pharmacol. 2014, 171, 2029–2050.
148. Szeto, H.H. Pharmacologic Approaches to Improve Mitochondrial Function in AKI and CKD. J. Am. Soc. Nephrol. 2017, 28, 2856–2865.
149. Sabbah, H.N.; Gupta, R.C.; Kohli, S.; Wang, M.; Hachem, S.; Zhang, K. Chronic Therapy With Elamipretide (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves Left Ventricular and Mitochondrial Function in Dogs With Advanced Heart Failure. Circ. Heart Fail. 2016, 9, e002206.
150. Righi, V.; Constantinou, C.; Mintzopoulos, D.; Khan, N.; Mupparaju, S.P.; Rahme, L.G.; Swartz, H.M.; Szeto, H.H.; Tompkins, R.G.; Tzika, A.A. Mitochondria-targeted antioxidant promotes recovery of skeletal muscle mitochondrial function after burn trauma assessed by in vivo 31P nuclear magnetic resonance and electron paramagnetic resonance spectroscopy. FASEB J. 2013, 27, 2521–2530.
151. Szeto, H.H. Stealth Peptides Target Cellular Powerhouses to Fight Rare and Common Age-Related Diseases. Protein. Pept. Lett. 2018, 25, 1108–1123.
152. Orr, 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. Free Radic. Biol. Med. 2013, 65, 1047–1059.
153. Orr, A.L.; Vargas, L.; Turk, C.N.; Baaten, J.E.; Matzen, J.T.; Dardov, V.J.; Attle, S.J.; Li, J.; Quackenbush, D.C.; Goncalves, R.L. Suppressors of superoxide production from mitochondrial complex III. Nat. Chem. Biol. 2015, 11, 834.
154. Wong, H.S.; Monternier, P.A.; Brand, M.D. S1QELs suppress mitochondrial superoxide/hydrogen peroxide production from site IQ without inhibiting reverse electron flow through Complex I. Free Radic. Biol. Med. 2019, 143, 545–559.
155. Watson, M.A.; Wong, H.S.; Brand, M.D. Use of S1QELs and S3QELs to link mitochondrial sites of superoxide and hydrogen peroxide generation to physiological and pathological outcomes. Biochem. Soc. Trans. 2019, 47, 1461–1469.
156. Brand, M.D. Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic. Biol. Med. 2016, 100, 14–31.
157. Fang, J.; Wong, H.S.; Brand, M.D. Production of superoxide and hydrogen peroxide in the mitochondrial matrix is dominated by site IQ of complex I in diverse cell lines. Redox Biol. 2020, 37, 101722.
158. Brand, M.D.; Goncalves, R.L.; Orr, A.L.; Vargas, L.; Gerencser, A.A.; Borch Jensen, M.; Wang, Y.T.; Melov, S.; Turk, C.N.; Matzen, J.T.; et al. Suppressors of Superoxide-H2O2 Production at Site IQ of Mitochondrial Complex I Protect against Stem Cell Hyperplasia and Ischemia-Reperfusion Injury. Cell Metab. 2016, 24, 582–592.
159. Piao, L.; Fang, Y.H.; Hamanaka, R.B.; Mutlu, G.M.; Dezfulian, C.; Archer, S.L.; Sharp, W.W. Suppression of Superoxide-Hydrogen Peroxide Production at Site IQ of Mitochondrial Complex I Attenuates Myocardial Stunning and Improves Postcardiac Arrest Outcomes. Crit. Care Med. 2020, 48, e133–e140.
160. Goncalves, R.L.; Watson, M.A.; Wong, H.-S.; Orr, A.L.; Brand, M.D. The use of site-specific suppressors to measure the relative contributions of different mitochondrial sites to skeletal muscle superoxide and hydrogen peroxide production. Redox Biol. 2020, 28, 101341.