Generic placeholder image

Current Molecular Pharmacology


ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Review Article

Mitochondria-Targeted Drugs

Author(s): Roman A. Zinovkin* and Andrey A. Zamyatnin*

Volume 12, Issue 3, 2019

Page: [202 - 214] Pages: 13

DOI: 10.2174/1874467212666181127151059


Background: Targeting of drugs to the subcellular compartments represents one of the modern trends in molecular pharmacology. The approach for targeting mitochondria was developed nearly 50 years ago, but only in the last decade has it started to become widely used for delivering drugs. A number of pathologies are associated with mitochondrial dysfunction, including cardiovascular, neurological, inflammatory and metabolic conditions.

Objective: This mini-review aims to highlight the role of mitochondria in pathophysiological conditions and diseases, to classify and summarize our knowledge about targeting mitochondria and to review the most important preclinical and clinical data relating to the antioxidant lipophilic cations MitoQ and SkQ1.

Methods: This is a review of available information in the PubMed and Clinical Trials databases (US National Library of Medicine) with no limiting period.

Results and Conclusion: Mitochondria play an important role in the pathogenesis of many diseases and possibly in aging. Both MitoQ and SkQ1 have shown many beneficial features in animal models and in a few completed clinical trials. More clinical trials and research efforts are needed to understand the signaling pathways influenced by these compounds. The antioxidant lipophilic cations have great potential for the treatment of a wide range of pathologies.

Keywords: Mitochondria, targeted drug delivery, uncouplers of oxidative phosphorylation, reactive oxygen species, antioxidants, metabolic syndrome.

Graphical Abstract
Davis, S.S. Biomedical applications of nanotechnology--implications for drug targeting and gene therapy. Trends Biotechnol., 1997, 15(6), 217-224.
Keservani, R.K.; Sharma, A.K.; Kesharwani, R.K. Drug Delivery Approaches and Nanosystems, Volume 2: Drug Targeting Aspects of Nanotechnology. CRC Press: , 2017.
Burns, R.J.; Smith, R.A.; Murphy, M.P. Synthesis and characterization of thiobutyltriphenylphosphonium bromide, a novel thiol reagent targeted to the mitochondrial matrix. Arch. Biochem. Biophys., 1995, 322(1), 60-68.
Wallace, D.C.; Fan, W. Energetics, epigenetics, mitochondrial genetics. Mitochondrion, 2010, 10(1), 12-31.
Nicholls, D.G.; Bernson, V.S.; Heaton, G.M. The identification of the component in the inner membrane of brown adipose tissue mitochondria responsible for regulating energy dissipation. Experientia Suppl., 1978, 32, 89-93.
Bagur, R.; Hajnóczky, G. Intracellular Ca2+ Sensing: Its Role in Calcium Homeostasis and Signaling. Mol. Cell, 2017, 66(6), 780-788.
Clapham, D.E. Calcium signaling. Cell, 2007, 131(6), 1047-1058.
Lemasters, J.J. Molecular Mechanisms of Cell Death. In Molecular Pathology; Elsevier, 2018, pp. 1-24.
Kim, J-S.; He, L.; Lemasters, J.J. Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochem. Biophys. Res. Commun., 2003, 304(3), 463-470.
Kalkavan, H.; Green, D.R. MOMP, cell suicide as a BCL-2 family business. Cell Death Differ., 2018, 25(1), 46-55.
Chautan, M.; Chazal, G.; Cecconi, F.; Gruss, P.; Golstein, P. Interdigital cell death can occur through a necrotic and caspase-independent pathway. Curr. Biol., 1999, 9(17), 967-970.
Angelova, P.R.; Abramov, A.Y. Functional role of mitochondrial reactive oxygen species in physiology. Free Radic. Biol. Med., 2016, 100, 81-85.
Zorov, D.B.; Juhaszova, M.; Sollott, S.J. Mitochondrial ROS-induced ROS release: an update and review. Biochim. Biophys. Acta (BBA)-. Bioenergetics, 2006, 1757(5-6), 509-517.
Orrenius, S.; Gogvadze, V.; Zhivotovsky, B. Mitochondrial oxidative stress: implications for cell death. Annu. Rev. Pharmacol. Toxicol., 2007, 47, 143-183.
Zhou, R.; Yazdi, A.S.; Menu, P.; Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature, 2011, 469(7329), 221-225.
Angelova, P.R.; Kasymov, V.; Christie, I.; Sheikhbahaei, S.; Turovsky, E.; Marina, N.; Korsak, A.; Zwicker, J.; Teschemacher, A.G.; Ackland, G.L.; Funk, G.D.; Kasparov, S.; Abramov, A.Y.; Gourine, A. V Functional Oxygen Sensitivity of Astrocytes. J. Neurosci., 2015, 35(29), 10460-10473.
Bedard, K.; Krause, K-H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol. Rev., 2007, 87(1), 245-313.
Klebanoff, S.J. Myeloperoxidase: friend and foe. J. Leukoc. Biol., 2005, 77(5), 598-625.
Kellogg, E.W.; Fridovich, I. Superoxide, hydrogen peroxide, and singlet oxygen in lipid peroxidation by a xanthine oxidase system. J. Biol. Chem., 1975, 250(22), 8812-8817.
Pizzinat, N.; Copin, N.; Vindis, C.; Parini, A.; Cambon, C. Reactive oxygen species production by monoamine oxidases in intact cells. Naunyn Schmiedebergs Arch. Pharmacol., 1999, 359(5), 428-431.
Montezano, A.C.; Touyz, R.M. Reactive oxygen species and endothelial function--role of nitric oxide synthase uncoupling and Nox family nicotinamide adenine dinucleotide phosphate oxidases. Basic Clin. Pharmacol. Toxicol., 2012, 110(1), 87-94.
Sahoo, S.; Meijles, D.N.; Pagano, P.J. NADPH oxidases: key modulators in aging and age-related cardiovascular diseases? Clin. Sci. (Lond.), 2016, 130(5), 317-335.
Nauseef, W.M. Biological roles for the NOX family NADPH oxidases. J. Biol. Chem., 2008, 283(25), 16961-16965.
Rastogi, R.; Geng, X.; Li, F.; Ding, Y. NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease. Front. Cell. Neurosci., 2016, 10, 301.
Vorobjeva, N.; Prikhodko, A.; Galkin, I.; Pletjushkina, O.; Zinovkin, R.; Sud’ina, G.; Chernyak, B.; Pinegin, B. Mitochondrial reactive oxygen species are involved in chemoattractant-induced oxidative burst and degranulation of human neutrophils in vitro. Eur. J. Cell Biol., 2017, 96(3), 254-265.
Zinovkin, R.A.; Romaschenko, V.P.; Galkin, I.I.; Zakharova, V.V.; Pletjushkina, O.Y.; Chernyak, B.V.; Popova, E.N. Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium. Aging (Albany NY), 2014, 6(8), 661-674.
Mukhopadhyay, P.; Horváth, B.; Zsengellér, Z.; Zielonka, J.; Tanchian, G.; Holovac, E.; Kechrid, M.; Patel, V.; Stillman, I.E.; Parikh, S.M.; Joseph, J.; Kalyanaraman, B.; Pacher, P. Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy. Free Radic. Biol. Med., 2012, 52(2), 497-506.
Tuppen, H.A.L.; Blakely, E.L.; Turnbull, D.M.; Taylor, R.W. Mitochondrial DNA mutations and human disease. Biochim. Biophys. Acta - Bioenerg., 2010, 1797(2), 113-128.
Lightowlers, R.N.; Taylor, R.W.; Turnbull, D.M. Mutations causing mitochondrial disease: What is new and what challenges remain? Science, 2015, 349(6255), 1494-1499.
Phielix, E.; Schrauwen-Hinderling, V.B.; Mensink, M.; Lenaers, E.; Meex, R.; Hoeks, J.; Kooi, M.E.; Moonen-Kornips, E.; Sels, J-P.; Hesselink, M.K.C.; Schrauwen, P. Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients. Diabetes, 2008, 57(11), 2943-2949.
Kelley, D.E.; He, J.; Menshikova, E.V.; Ritov, V.B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes, 2002, 51(10), 2944-2950.
Ritov, V.B.; Menshikova, E.V.; Azuma, K.; Wood, R.; Toledo, F.G.S.; Goodpaster, B.H.; Ruderman, N.B.; Kelley, D.E. Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity. Am. J. Physiol. Endocrinol. Metab., 2010, 298(1), E49-E58.
Mihalik, S.J.; Goodpaster, B.H.; Kelley, D.E.; Chace, D.H.; Vockley, J.; Toledo, F.G.S.; DeLany, J.P. Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity (Silver Spring), 2010, 18(9), 1695-1700.
Newgard, C.B.; An, J.; Bain, J.R.; Muehlbauer, M.J.; Stevens, R.D.; Lien, L.F.; Haqq, A.M.; Shah, S.H.; Arlotto, M.; Slentz, C.A.; Rochon, J.; Gallup, D.; Ilkayeva, O.; Wenner, B.R.; Yancy, W.S.; Eisenson, H.; Musante, G.; Surwit, R.S.; Millington, D.S.; Butler, M.D.; Svetkey, L.P. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab., 2009, 9(4), 311-326.
Adams, S.H.; Hoppel, C.L.; Lok, K.H.; Zhao, L.; Wong, S.W.; Minkler, P.E.; Hwang, D.H.; Newman, J.W.; Garvey, W.T. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J. Nutr., 2009, 139(6), 1073-1081.
Anderson, E.J.; Lustig, M.E.; Boyle, K.E.; Woodlief, T.L.; Kane, D.A.; Lin, C-T.; Price, J.W.; Kang, L.; Rabinovitch, P.S.; Szeto, H.H.; Houmard, J.A.; Cortright, R.N.; Wasserman, D.H.; Neufer, P.D. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J. Clin. Invest., 2009, 119(3), 573-581.
Brown, D.A.; Perry, J.B.; Allen, M.E.; Sabbah, H.N.; Stauffer, B.L.; Shaikh, S.R.; Cleland, J.G.F.; Colucci, W.S.; Butler, J.; Voors, A.A.; Anker, S.D.; Pitt, B.; Pieske, B.; Filippatos, G.; Greene, S.J.; Gheorghiade, M. Expert consensus document: Mitochondrial function as a therapeutic target in heart failure. Nat. Rev. Cardiol., 2017, 14(4), 238-250.
Halestrap, A.P.; Pasdois, P. The role of the mitochondrial permeability transition pore in heart disease. Biochim. Biophys. Acta, 2009, 1787(11), 1402-1415.
Boudina, S.; Sena, S.; O’Neill, B.T.; Tathireddy, P.; Young, M.E.; Abel, E.D. Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity. Circulation, 2005, 112(17), 2686-2695.
Rontoyanni, V.G.; Nunez Lopez, O.; Fankhauser, G.T.; Cheema, Z.F.; Rasmussen, B.B.; Porter, C. Mitochondrial Bioenergetics in the Metabolic Myopathy Accompanying Peripheral Artery Disease. Front. Physiol., 2017, 8, 141.
Swerdlow, R.H.; Burns, J.M.; Khan, S.M. The Alzheimer’s disease mitochondrial cascade hypothesis. J. Alzheimers Dis., 2010, 20(Suppl. 2), S265-S279.
Onyango, I.G.; Dennis, J.; Khan, S.M. Mitochondrial Dysfunction in Alzheimer’s Disease and the Rationale for Bioenergetics Based Therapies. Aging Dis., 2016, 7(2), 201-214.
Lustbader, J.W.; Cirilli, M.; Lin, C.; Xu, H.W.; Takuma, K.; Wang, N.; Caspersen, C.; Chen, X.; Pollak, S.; Chaney, M.; Trinchese, F.; Liu, S.; Gunn-Moore, F.; Lue, L-F.; Walker, D.G.; Kuppusamy, P.; Zewier, Z.L.; Arancio, O.; Stern, D.; Yan, S.S.; Wu, H. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science, 2004, 304(5669), 448-452.
Manczak, M.; Anekonda, T.S.; Henson, E.; Park, B.S.; Quinn, J.; Reddy, P.H. Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum. Mol. Genet., 2006, 15(9), 1437-1449.
Moreira, P.I.; Zhu, X.; Wang, X.; Lee, H-G.; Nunomura, A.; Petersen, R.B.; Perry, G.; Smith, M.A. Mitochondria: a therapeutic target in neurodegeneration. Biochim. Biophys. Acta, 2010, 1802(1), 212-220.
Beal, M.F. Mitochondria and neurodegeneration. Novartis Found. Symp., 2007, 287, 183-192.
Ekstrand, M.I.; Terzioglu, M.; Galter, D.; Zhu, S.; Hofstetter, C.; Lindqvist, E.; Thams, S.; Bergstrand, A.; Hansson, F.S.; Trifunovic, A.; Hoffer, B.; Cullheim, S.; Mohammed, A.H.; Olson, L.; Larsson, N-G. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc. Natl. Acad. Sci. USA, 2007, 104(4), 1325-1330.
Galter, D.; Pernold, K.; Yoshitake, T.; Lindqvist, E.; Hoffer, B.; Kehr, J.; Larsson, N-G.; Olson, L. MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson’s disease. Genes Brain Behav., 2010, 9(2), 173-181.
Carmo, C.; Naia, L.; Lopes, C.; Rego, A.C. Mitochondrial Dysfunction in Huntington’s Disease. Adv. Exp. Med. Biol., 2018, 1049, 59-83.
Beal, M.F.; Brouillet, E.; Jenkins, B.G.; Ferrante, R.J.; Kowall, N.W.; Miller, J.M.; Storey, E.; Srivastava, R.; Rosen, B.R.; Hyman, B.T. Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J. Neurosci., 1993, 13(10), 4181-4192.
Shi, P.; Gal, J.; Kwinter, D.M.; Liu, X.; Zhu, H. Mitochondrial dysfunction in amyotrophic lateral sclerosis. Biochim. Biophys. Acta, 2010, 1802(1), 45-51.
Igoudjil, A.; Magrané, J.; Fischer, L.R.; Kim, H.J.; Hervias, I.; Dumont, M.; Cortez, C.; Glass, J.D.; Starkov, A.A.; Manfredi, G. In vivo pathogenic role of mutant SOD1 localized in the mitochondrial intermembrane space. J. Neurosci., 2011, 31(44), 15826-15837.
Hoffman, E.P.; Brown, R.H.; Kunkel, L.M. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell, 1987, 51(6), 919-928.
Sperl, W.; Skladal, D.; Gnaiger, E.; Wyss, M.; Mayr, U.; Hager, J.; Gellerich, F.N. High resolution respirometry of permeabilized skeletal muscle fibers in the diagnosis of neuromuscular disorders. Mol. Cell. Biochem., 1997, 174(1-2), 71-78.
Vila, M.C.; Rayavarapu, S.; Hogarth, M.W.; Meulen, J.H. Van der; Horn, A.; Defour, A.; Takeda, S.; Brown, K.J.; Hathout, Y.; Nagaraju, K.; Jaiswal, J.K. Mitochondria mediate cell membrane repair and contribute to Duchenne muscular dystrophy. Cell Death Differ., 2017, 24(2), 330-342.
Kelly-Worden, M.; Thomas, E. Mitochondrial Dysfunction in Duchenne Muscular Dystrophy. Open J. Endocr. Metab. Dis., 2014, 4(8), 211-218.
Rygiel, K.A.; Miller, J.; Grady, J.P.; Rocha, M.C.; Taylor, R.W.; Turnbull, D.M. Mitochondrial and inflammatory changes in sporadic inclusion body myositis. Neuropathol. Appl. Neurobiol., 2015, 41(3), 288-303.
Balk, R.A. Systemic inflammatory response syndrome (SIRS): where did it come from and is it still relevant today? Virulence, 2014, 5(1), 20-26.
Rangel-Frausto, M.S.; Pittet, D.; Costigan, M.; Hwang, T.; Davis, C.S.; Wenzel, R.P. The natural history of the systemic inflammatory response syndrome (SIRS): A prospective study. Jama, 1995, 273(2), 117-123.
Zakharova, V.V.; Pletjushkina, O.Y.; Zinovkin, R.A.; Popova, E.N.; Chernyak, B. V Mitochondria-Targeted Antioxidants and Uncouplers of Oxidative Phosphorylation in Treatment of the Systemic Inflammatory Response Syndrome (SIRS). J. Cell. Physiol., 2017, 232(5), 904-912.
Jo, E-K.; Kim, J.K.; Shin, D-M.; Sasakawa, C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell. Mol. Immunol., 2016, 13(2), 148-159.
Zhong, Z.; Liang, S.; Sanchez-Lopez, E.; He, F.; Shalapour, S.; Lin, X.; Wong, J.; Ding, S.; Seki, E.; Schnabl, B.; Hevener, A.L.; Greenberg, H.B.; Kisseleva, T.; Karin, M. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature, 2018, 560(7717), 198-203.
Zhang, Q.; Raoof, M.; Chen, Y.; Sumi, Y.; Sursal, T.; Junger, W.; Brohi, K.; Itagaki, K.; Hauser, C.J. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature, 2010, 464(7285), 104-107.
Prikhodko, A.S.; Vitushkina, M.V.; Zinovkina, L.A.; Popova, E.N.; Zinovkin, R.A. Priming of human neutrophils is necessary for their activation by extracellular DNA. Biochem., 2016, 81(6), 609-614.
Chakraborty, K.; Raundhal, M.; Chen, B.B.; Morse, C.; Tyurina, Y.Y.; Khare, A.; Oriss, T.B.; Huff, R.; Lee, J.S.; St Croix, C.M.; Watkins, S.; Mallampalli, R.K.; Kagan, V.E.; Ray, A.; Ray, P. The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia. Nat. Commun., 2017, 8, 13944.
Raoof, M.; Zhang, Q.; Itagaki, K.; Hauser, C.J. Mitochondrial Peptides Are Potent Immune Activators That Activate Human Neutrophils Via FPR-1. J. Trauma Inj. Infect. Crit. Care, 2010, 68(6), 1328-1334.
Mitochondrial Biology and Experimental Therapeutics; Oliveira, P.J., Ed. Springer: Cham, 2018.
Sun, N.; Youle, R.J.; Finkel, T. The Mitochondrial Basis of Aging. Mol. Cell, 2016, 61(5), 654-666.
Harman, D. The biologic clock: the mitochondria? J. Am. Geriatr. Soc., 1972, 20(4), 145-147.
Trifunovic, A.; Wredenberg, A.; Falkenberg, M.; Spelbrink, J.N.; Rovio, A.T.; Bruder, C.E.; Bohlooly-Y, M.; Gidlöf, S.; Oldfors, A.; Wibom, R.; Törnell, J.; Jacobs, H.T.; Larsson, N-G. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature, 2004, 429(6990), 417-423.
Schriner, S.E.; Linford, N.J.; Martin, G.M.; Treuting, P.; Ogburn, C.E.; Emond, M.; Coskun, P.E.; Ladiges, W.; Wolf, N.; Remmen, H. Van; Wallace, D.C.; Rabinovitch, P.S. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science, 2005, 308(5730), 1909-1911.
Kennedy, S.R.; Salk, J.J.; Schmitt, M.W.; Loeb, L.A. Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet., 2013, 9(9)e1003794
Chung, H.Y.; Cesari, M.; Anton, S.; Marzetti, E.; Giovannini, S.; Seo, A.Y.; Carter, C.; Yu, B.P.; Leeuwenburgh, C. Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res. Rev., 2009, 8(1), 18-30.
Judge, S.; Jang, Y.M.; Smith, A.; Hagen, T.; Leeuwenburgh, C. Age-associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: implications for the mitochondrial theory of aging. FASEB J., 2005, 19(3), 419-421.
Ungvari, Z.; Orosz, Z.; Labinskyy, N.; Rivera, A.; Xiangmin, Z.; Smith, K.; Csiszar, A. Increased mitochondrial H2O2 production promotes endothelial NF-kappaB activation in aged rat arteries. Am. J. Physiol. Heart Circ. Physiol., 2007, 293(1), H37-H47.
Dai, D-F.; Rabinovitch, P.S.; Ungvari, Z. Mitochondria and cardiovascular aging. Circ. Res., 2012, 110(8), 1109-1124.
Sanada, F.; Taniyama, Y.; Muratsu, J.; Otsu, R.; Shimizu, H.; Rakugi, H.; Morishita, R. Source of Chronic Inflammation in Aging. Front. Cardiovasc. Med., 2018, 5, 12.
Merkwirth, C.; Jovaisaite, V.; Durieux, J.; Matilainen, O.; Jordan, S.D.; Quiros, P.M.; Steffen, K.K.; Williams, E.G.; Mouchiroud, L.; Tronnes, S.U.; Murillo, V.; Wolff, S.C.; Shaw, R.J.; Auwerx, J.; Dillin, A. Two Conserved Histone Demethylases Regulate Mitochondrial Stress-Induced Longevity. Cell, 2016, 165(5), 1209-1223.
Tian, Y.; Garcia, G.; Bian, Q.; Steffen, K.K.; Joe, L.; Wolff, S.; Meyer, B.J.; Dillin, A. Mitochondrial Stress Induces Chromatin Reorganization to Promote Longevity and UPR mt. Cell, 2016, 165(5), 1197-1208.
Gray, M.W.; Burger, G.; Lang, B.F. Mitochondrial evolution. Science, 1999, 283(5407), 1476-1481.
Adam-Vizi, V.; Chinopoulos, C. Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol. Sci., 2006, 27(12), 639-645.
Kagan, V.E.; Borisenko, G.G.; Tyurina, Y.Y.; Tyurin, V.A.; Jiang, J.; Potapovich, A.I.; Kini, V.; Amoscato, A.A.; Fujii, Y. Oxidative lipidomics of apoptosis: redox catalytic interactions of cytochrome c with cardiolipin and phosphatidylserine. Free Radic. Biol. Med., 2004, 37(12), 1963-1985.
Pfanner, N.; Geissler, A. Versatility of the mitochondrial protein import machinery. Nat. Rev. Mol. Cell Biol., 2001, 2(5), 339-349.
Liberman, E.A.; Topaly, V.P.; Tsofina, L.M.; Jasaitis, A.A.; Skulachev, V.P. Mechanism of coupling of oxidative phosphorylation and the membrane potential of mitochondria. Nature, 1969, 222(5198), 1076-1078.
Smith, R.A.; Porteous, C.M.; Coulter, C.V.; Murphy, M.P. Selective targeting of an antioxidant to mitochondria. Eur. J. Biochem., 1999, 263(3), 709-716.
Amorim, R.; Benfeito, S.; Teixeira, J.; Cagide, F.; Oliveira, P.J.; Borges, F. In:. Mitochondrial Biology and Experimental Therapeutics; Oliveira, P.J., Ed.; Springer: Cham, 2018, pp. 333-358.
Weissig, V. In: In: Mitochondrial Medicine; Weissig, V.; Edeas, M., Eds.; Humana Press, 2015; Vol. II, pp. 1-11.
D’Souza, G.G.M.; Boddapati, S.V.; Weissig, V. Mitochondrial leader sequence-plasmid DNA conjugates delivered into mammalian cells by DQAsomes co-localize with mitochondria. Mitochondrion, 2005, 5(5), 352-358.
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(33), 34682-34990.
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(8), 1250-1261.
Szeto, H.H. Cell-permeable, mitochondrial-targeted, peptide antioxidants. AAPS J., 2006, 8(2), E277-E283.
Cerrato, C.P.; Langel, Ü. Cell-Penetrating Peptides Targeting Mitochondria. In Mitochondrial Biology and Experimental Therapeutics; Springer International Publishing: Cham, 2018, pp. 593-611.
Szeto, H.H.; Birk, A.V. Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin. Pharmacol. Ther., 2014, 96(6), 672-683.
Heijne, G. von Mitochondrial targeting sequences may form amphiphilic helices. EMBO J., 1986, 5(6), 1335-1342.
Neupert, W.; Herrmann, J.M. Translocation of proteins into mitochondria. Annu. Rev. Biochem., 2007, 76, 723-749.
Flierl, A.; Jackson, C.; Cottrell, B.; Murdock, D.; Seibel, P.; Wallace, D.C. Targeted delivery of DNA to the mitochondrial compartment via import sequence-conjugated peptide nucleic acid. Mol. Ther., 2003, 7(4), 550-557.
Yu, H.; Koilkonda, R.D.; Chou, T-H.; Porciatti, V.; Ozdemir, S.S.; Chiodo, V.; Boye, S.L.; Boye, S.E.; Hauswirth, W.W.; Lewin, A.S.; Guy, J. Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber’s hereditary optic neuropathy in a mouse model. Proc. Natl. Acad. Sci. USA, 2012, 109(20), E1238-E1247.
Cha, M-Y.; Han, S-H.; Son, S.M.; Hong, H-S.; Choi, Y-J.; Byun, J.; Mook-Jung, I. Mitochondria-specific accumulation of amyloid β induces mitochondrial dysfunction leading to apoptotic cell death. PLoS One, 2012, 7(4)e34929
Korshunov, S.S.; Skulachev, V.P.; Starkov, A.A. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett., 1997, 416(1), 15-18.
Antonenko, Y.N.; Avetisyan, A.V.; Bakeeva, L.E.; Chernyak, B.V.; Chertkov, V.A.; Domnina, L.V.; Ivanova, O.Y.; Izyumov, D.S.; Khailova, L.S.; Klishin, S.S.; Korshunova, G.A.; Lyamzaev, K.G.; Muntyan, M.S.; Nepryakhina, O.K.; Pashkovskaya, A.A.; Pletjushkina, O.Y.; Pustovidko, A.V.; Roginsky, V.A.; Rokitskaya, T.I.; Ruuge, E.K.; Saprunova, V.B.; Severina, I.I.; Simonyan, R.A.; Skulachev, I.V.; Skulachev, M.V.; Sumbatyan, N.V.; Sviryaeva, I.V.; Tashlitsky, V.N.; Vassiliev, J.M.; Vyssokikh, M.Y.; Yaguzhinsky, L.S.; Zamyatnin, A.A.; Skulachev, V.P. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: synthesis and in vitro studies. Biochemistry (Mosc.), 2008, 73(12), 1273-1287.
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(3), 709-719.
Rossman, M.J.; Santos-Parker, J.R.; Steward, C.A.C.; Bispham, N.Z.; Cuevas, L.M.; Rosenberg, H.L.; Woodward, K.A.; Chonchol, M.; Gioscia-Ryan, R.A.; Murphy, M.P.; Seals, D.R. Chronic Supplementation With a Mitochondrial Antioxidant (MitoQ) Improves Vascular Function in Healthy Older Adults. Hypertens (Dallas, Tex. 1979). 2018, 71(6), 1056-1063.
Snow, B.J.; Rolfe, F.L.; Lockhart, M.M.; Frampton, C.M.; O’Sullivan, J.D.; Fung, V.; Smith, R.A.J.; Murphy, M.P.; Taylor, K.M. Protect Study Group A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson’s disease. Mov. Disord., 2010, 25(11), 1670-1674.
Gane, E.J.; Weilert, F.; Orr, D.W.; Keogh, G.F.; Gibson, M.; Lockhart, M.M.; Frampton, C.M.; Taylor, K.M.; Smith, R.A.J.; Murphy, M.P. The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients. Liver Int., 2010, 30(7), 1019-1026.
Petrov, A.; Perekhvatova, N.; Skulachev, M.; Stein, L.; Ousler, G. SkQ1 Ophthalmic Solution for Dry Eye Treatment: Results of a Phase 2 Safety and Efficacy Clinical Study in the Environment and During Challenge in the Controlled Adverse Environment Model. Adv. Ther., 2016, 33(1), 96-115.
Sies, H. Total antioxidant capacity: appraisal of a concept. J. Nutr., 2007, 137(6), 1493-1495.
Gasparovic, A.C.; Jaganjac, M.; Mihaljevic, B.; Sunjic, S.B.; Zarkovic, N. Assays for the measurement of lipid peroxidation. Methods Mol. Biol., 2013, 965, 283-296.
Kelso, G.F.; Porteous, C.M.; Coulter, C.V.; Hughes, G.; Porteous, W.K.; Ledgerwood, E.C.; Smith, R.A.; Murphy, M.P. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J. Biol. Chem., 2001, 276(7), 4588-4596.
Skulachev, V.P.; Antonenko, Y.N.; Cherepanov, D.A.; Chernyak, B.V.; Izyumov, D.S.; Khailova, L.S.; Klishin, S.S.; Korshunova, G.A.; Lyamzaev, K.G.; Pletjushkina, O.Y.; Roginsky, V.A.; Rokitskaya, T.I.; Severin, F.F.; Severina, I.I.; Simonyan, R.A.; Skulachev, M.V.; Sumbatyan, N.V.; Sukhanova, E.I.; Tashlitsky, V.N.; Trendeleva, T.A.; Vyssokikh, M.Y.; Zvyagilskaya, R.A. Prevention of cardiolipin oxidation and fatty acid cycling as two antioxidant mechanisms of cationic derivatives of plastoquinone (SkQs). Biochim. Biophys. Acta Bioenerg., 2010, 1797(6-7), 878-889.
Severin, F.F.; Severina, I.I.; Antonenko, Y.N.; Rokitskaya, T.I.; Cherepanov, D.A.; Mokhova, E.N.; Vyssokikh, M.Y.; Pustovidko, A.V.; Markova, O.V.; Yaguzhinsky, L.S.; Korshunova, G.A.; Sumbatyan, N.V.; Skulachev, M.V.; Skulachev, V.P. Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore. Proc. Natl. Acad. Sci. USA, 2010, 107(2), 663-668.
Feniouk, B.A.; Skulachev, V.P. Cellular and Molecular Mechanisms of Action of Mitochondria-Targeted Antioxidants. Curr. Aging Sci., 2017, 10(1), 41-48.
Asin-Cayuela, J.; Manas, A-R.B.; James, A.M.; Smith, R.A.J.; Murphy, M.P. Fine-tuning the hydrophobicity of a mitochondria-targeted antioxidant. FEBS Lett., 2004, 571(1-3), 9-16.
Pond, S.M.; Tozer, T.N. First-pass elimination. Basic concepts and clinical consequences. Clin. Pharmacokinet., 9(1), 1-25.
Murphy, M.P.; Smith, R.A.J. Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu. Rev. Pharmacol. Toxicol., 2007, 47, 629-656.
Smith, R.A.J.; Porteous, C.M.; Gane, A.M.; Murphy, M.P. Delivery of bioactive molecules to mitochondria in vivo. Proc. Natl. Acad. Sci. USA, 2003, 100(9), 5407-5412.
Kezic, A.; Spasojevic, I.; Lezaic, V.; Bajcetic, M. Mitochondria-Targeted Antioxidants: Future Perspectives in Kidney Ischemia Reperfusion Injury. Oxid. Med. Cell. Longev., 2016, 2016, 1-12.
Silva, F.S.G.; Simoes, R.F.; Couto, R.; Oliveira, P.J. Targeting Mitochondria in Cardiovascular Diseases. Curr. Pharm. Des., 2016, 22(37), 5698-5717.
Braakhuis, A.J.; Nagulan, R.; Somerville, V. The Effect of MitoQ on Aging-Related Biomarkers: A Systematic Review and Meta-Analysis. Oxid. Med. Cell. Longev., 2018, 20188575263
Shabalina, I.G.; Vyssokikh, M.Y.; Gibanova, N.; Csikasz, R.I.; Edgar, D.; Hallden-Waldemarson, A.; Rozhdestvenskaya, Z.; Bakeeva, L.E.; Vays, V.B.; Pustovidko, A.V.; Skulachev, M.V.; Cannon, B.; Skulachev, V.P.; Nedergaard, J. Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1. Aging (Albany NY), 2017, 9(2), 315-339.
Ng, L.F.; Gruber, J.; Cheah, I.K.; Goo, C.K.; Cheong, W.F.; Shui, G.; Sit, K.P.; Wenk, M.R.; Halliwell, B. The mitochondria-targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease. Free Radic. Biol. Med., 2014, 71, 390-401.
Shill, D.D.; Southern, W.M.; Willingham, T.B.; Lansford, K.A.; McCully, K.K.; Jenkins, N.T. Mitochondria-specific antioxidant supplementation does not influence endurance exercise training-induced adaptations in circulating angiogenic cells, skeletal muscle oxidative capacity or maximal oxygen uptake. J. Physiol., 2016, 594(23), 7005-7014.
Gioscia-Ryan, R.A.; LaRocca, T.J.; Sindler, A.L.; Zigler, M.C.; Murphy, M.P.; Seals, D.R. Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice. J. Physiol., 2014, 592(12), 2549-2561.
Loo B. , van der; Labugger, R.; Skepper, J.N.; Bachschmid, M.; Kilo, J.; Powell, J.M.; Palacios-Callender, M.; Erusalimsky, J.D.; Quaschning, T.; Malinski, T.; Gygi, D.; Ullrich, V.; Lüscher, T.F. Enhanced peroxynitrite formation is associated with vascular aging. J. Exp. Med., 2000, 192(12), 1731-1744.
Bachschmid, M.M.; Schildknecht, S.; Matsui, R.; Zee, R.; Haeussler, D.; Cohen, R.A.; Pimental, D.; Loo, B. van der Vascular aging: chronic oxidative stress and impairment of redox signaling-consequences for vascular homeostasis and disease. Ann. Med., 2013, 45(1), 17-36.
Weidinger, A.; Müllebner, A.; Paier-Pourani, J.; Banerjee, A.; Miller, I.; Lauterböck, 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(7), 572-586.
Manskikh, V.N.; Gancharova, O.S.; Nikiforova, A.I.; Krasilshchikova, M.S.; Shabalina, I.G.; Egorov, M.V.; Karger, E.M.; Milanovsky, G.E.; Galkin, I.I.; Skulachev, V.P.; Zinovkin, R.A. Age-associated murine cardiac lesions are attenuated by the mitochondria-targeted antioxidant SkQ1. Histol. Histopathol., 2015, 30(3), 353-360.
Galkin, I.I.; Pletjushkina, O.Y.; Zinovkin, R.A.; Zakharova, V.V.; Birjukov, I.S.; Chernyak, B.V.; Popova, E.N. Mitochondria-targeted antioxidants prevent TNFα-induced endothelial cell damage. Biochemistry (Mosc.), 2014, 79(2), 124-130.
Mao, P.; Manczak, M.; Shirendeb, U.P.; Reddy, P.H. MitoQ, a mitochondria-targeted antioxidant, delays disease progression and alleviates pathogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Biochim. Biophys. Acta, 2013, 1832(12), 2322-2331.
Korenaga, M.; Wang, T.; Li, Y.; Showalter, L.A.; Chan, T.; Sun, J.; Weinman, S.A. Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J. Biol. Chem., 2005, 280(45), 37481-37488.
Chacko, B.K.; Srivastava, A.; Johnson, M.S.; Benavides, G.A.; Chang, M.J.; Ye, Y.; Jhala, N.; Murphy, M.P.; Kalyanaraman, B.; Darley-Usmar, V.M. Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis. Hepatology, 2011, 54(1), 153-163.
Lukashev, A.N.; Skulachev, M.V.; Ostapenko, V.; Savchenko, A.Y.; Pavshintsev, V.V.; Skulachev, V.P. Advances in development of rechargeable mitochondrial antioxidants. Prog. Mol. Biol. Transl. Sci., 2014, 127, 251-265.
Skulachev, V.P.; Anisimov, V.N.; Antonenko, Y.N.; Bakeeva, L.E.; Chernyak, B.V.; Erichev, V.P.; Filenko, O.F.; Kalinina, N.I.; Kapelko, V.I.; Kolosova, N.G.; Kopnin, B.P.; Korshunova, G.A.; Lichinitser, M.R.; Obukhova, L.A.; Pasyukova, E.G.; Pisarenko, O.I.; Roginsky, V.A.; Ruuge, E.K.; Senin, I.I.; Severina, I.I.; Skulachev, M.V.; Spivak, I.M.; Tashlitsky, V.N.; Tkachuk, V.A.; Vyssokikh, M.Y.; Yaguzhinsky, L.S.; Zorov, D.B. An attempt to prevent senescence: a mitochondrial approach. Biochim. Biophys. Acta, 2009, 1787(5), 437-461.
Markovets, A.M.; Fursova, A.Z.; Kolosova, N.G. Therapeutic action of the mitochondria-targeted antioxidant SkQ1 on retinopathy in OXYS rats linked with improvement of VEGF and PEDF gene expression. PLoS One, 2011, 6(7)e21682
Iomdina, E.N.; Khoroshilova-Maslova, I.P.; Robustova, O.V.; Averina, O.A.; Kovaleva, N.A.; Aliev, G.; Reddy, V.P.; Zamyatnin, A.A.; Skulachev, M.V.; Senin, I.I.; Skulachev, V.P. Mitochondria-targeted antioxidant SkQ1 reverses glaucomatous lesions in rabbits. Front. Biosci. Landmark Ed., 2015, 20(1), 892-901.
Yani, E.V.; Katargina, L.A.; Chesnokova, N.B.; Beznos, O.V.; Savchenko, A.Y.; Vygodin, V.A.; Gudkova, E.Y.; Zamyatnin, J.A.A.; Skulachev, M.V. The first experience of using the drug Vizomitin in the treatment of dry eyes. Per. Med., 2012, 4(59), 134-137.
Brzheskiy, V.V.; Efimova, E.L.; Vorontsova, T.N.; Alekseev, V.N.; Gusarevich, O.G.; Shaidurova, K.N.; Ryabtseva, A.A.; Andryukhina, O.M.; Kamenskikh, T.G.; Sumarokova, E.S.; Miljudin, E.S.; Egorov, E.A.; Lebedev, O.I.; Surov, A.V.; Korol, A.R.; Nasinnyk, I.O.; Bezditko, P.A.; Muzhychuk, O.P.; Vygodin, V.A.; Yani, E.V.; Savchenko, A.Y.; Karger, E.M.; Fedorkin, O.N.; Mironov, A.N.; Ostapenko, V.; Popeko, N.A.; Skulachev, V.P.; Skulachev, M.V. Results of a Multicenter, Randomized, Double-Masked, Placebo-Controlled Clinical Study of the Efficacy and Safety of Visomitin Eye Drops in Patients with Dry Eye Syndrome. Adv. Ther., 2015, 32(12), 1263-1279.
Zernii, E.Y.; Gancharova, O.S.; Baksheeva, V.E.; Golovastova, M.O.; Kabanova, E.I.; Savchenko, M.S.; Tiulina, V.V.; Sotnikova, L.F.; Zamyatnin, A.A.; Philippov, P.P.; Senin, I.I. Mitochondria-Targeted Antioxidant SkQ1 Prevents Anesthesia-Induced Dry Eye Syndrome. Oxid. Med. Cell. Longev., 2017, 2017, 1-17.
Callender, S.P.; Mathews, J.A.; Kobernyk, K.; Wettig, S.D. Microemulsion utility in pharmaceuticals: Implications for multi-drug delivery. Int. J. Pharm., 2017, 526(1-2), 425-442.

© 2022 Bentham Science Publishers | Privacy Policy