Mitochondria targeting

Strategies for the design of mitochondria-targeted drug and DNA delivery systems and the principles such systems are based upon have been reviewed earlier by us comprehensively (16-18). Therefore, the scope of this chapter shall be limited exclusively to approaches involving mitochondriotropic molecules-mediated drug and DNA delivery to mammalian mitochondria in response to the mitochondrial membrane potential. 

Following the discovery of DQAsomes, we have explored these vesicles as the first available mitochondria-targeted colloidal drug and DNA delivery system. We were able to demonstrate in a series of papers that DQAsomes and DQAsome-like vesicles are well suited for the delivery of plasmid DNA and of small molecules specifically to mitochondria within living mammalian cells (38 3). 

Mitochondriotropic liposomes as well as DQAsomes and DQAsome-like vesicles represent the first mitochondria-targeted colloidal drug and DNA delivery systems. Their further exploration holds promise to open up new ways for the treatment of cancer and a multitude of mitochondrial diseases. 

Reed JC. Dysregulation of apoptosis in cancer. J Clin Oncol 1999 17 2941-2953. Morisaki T, Katano M. Mitochondria-targeting therapeutic strategies for overcoming chemoresistance and progression of cancer. Curr Med Chem 2003 10(23) 2517-2521. 

A. Azzi B. Chance (1969) Biochim. Biophys. Acta 189, 141. Selected entries from Methods in Enzymology [vol, page(s)] Calibration of calcium binding, 260, 425-427 luminescence measurement, 260, 424-425 mitochondria-targeted hybrid protein [calcium quantitation, 260, 418, 422, 424-428 stable expression, 260, 418-421 transient expression, 260, 420 intracellular localization, 260, 421-425 reconstitution with coelenterazine, 260, 422-422] structure, 260, 418. 

Flickey JL, Ruhayel RA, Barnard PJ, Baker MV, Bemers-Price SJ, Filipovska A (2008) Mitochondria-targeted chemotherapeutics the rational design of gold(I) N-heterocyclic carbene complexes that are selectively toxic to cancer cells and target protein selenols in preference to thiols. J Am Chem Soc 130 12570-12571... 

Mitochondria-targeted STPP liposomes significantly increased cell cytotoxicity by almost 20% when compared to non-targeted liposomes (8). 

The formation of a DNA ladder, characteristic of DNA fragmentation is observed only in the case of mitochondria-targeted STPP liposomes. A typical image is seen in Fig. 2. 

Intraperitoneal injection of mitochondria-targeted plastoquinone derivative SkQl at very low concentrations (250 nmol/kg body weight) prevents the deleterious effect of Ap on LTP. In vivo and in vitro injection of SkQl compensates for Ap-induced oxidative damage of long-term synaptic plasticity in the hippocampus [563]. 

Kapay NA, Popova OV, Isaev NK, Stelmashook EV, Kondratenko RV, Zorov DB et al (2013) Mitochondria-targeted plas-toquinone antioxidant SkQl prevents amyloid-[)-induccd impairment of long-term potentiation in rat hippocampal slices. J Alzheimers Dis 36 377-383... 

The Jurkat (human acute T-cell leukemia, clone E6-1) cell line was from ATCC. Cytochrome c ELISA ( MCTC0), active caspase-3 ELISA ( KM300), active caspase-7 ELISA ( KM700), bzVKD-fmk ( FMK011 or included with kits), human Bid ( 846-BD), mouse Bid ( 860-MM), caspase-8-cleaved human Bid ( 882-B8), caspase-8 cleaved mouse Bid ( 883-M8), mouse Bcl-xL ( 878-BC) missing the carboxyl terminal mitochondria targeting sequence, Bak-BH3 synthetic peptide ( 881-BA), Bak L to A synthetic peptide ( 879-BK), and HRP conjugated to streptavidin, recombinant human caspase 2 ( 702-C2), caspase 3 ( 707-C3), caspase 7 ( 823-C7), caspase 8 ( 705-C8), and caspase 10 ( 834-CP) were from R D Systems. Biotinylated standards for the ELISAs were made and assayed as previously... 

Jauslin, M.L., Meier, T, Smith, R.A., and Murphy, M.P., Mitochondria-targeted antioxidants protect Friedreich ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants, Faseb J 17 (13), 1972-1974, 2(X)3. 

N. Sassi, A. Mattarei, M. Azzolini, P. Bemardi, 1. Szabo, C. Paradisi, M. Zoratti, and L. Biasutto, Mitochondria -targeted resveratrol derivatives act as cytotoxic pro-oxidants. Curr. Pharm. Des., 20 (2014) 172-9. 

K. Lyamzaev, A. Pustovidko, R. Simonyan, T. Rokitskaya, L. Domnina, O. Ivanova, I. Severina, N. Sumbatyan, G. Korshimova, V. Tashlitsky, V. Roginsky, Y. Antonenko, M. Skulachev, B. Chernyak, and V. Skulachev, Novel mitochondria -targeted antioxidants plastoquinone conjugated with cationic plant alkaloids berberine and palmatine. Pharm. Res., 28 (2011) 2883-95. 

Victor, V.M., N. Apostolova, R. Herance, A. Hemandez-Mijares, and M. Rocha. 2009. Oxidative stress and mitochondrial dysfunction in atherosclerosis Mitochondria-targeted antioxidants as potential therapy. CurmntMeScinMChen 16 4654—67. 

Benedikt W, Walter N (2000) Mitochondria-targeted green fluorescent proteins convenient tools for the study of organelle biogenesis in Saccharomyces cerevisiae. Yeast 16 1421-1427... 

He, Q., Harris, N., Ren, J., Han, X. (2014) Mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes. Oxid. Med. Cell. Longev. 2014, 654198. 

Ghosal, S. Mitochondria-targeted antioxidants comprising coenzyme QIO, reduced CoQlO, oxygenated dibenzo-a-pyrone, or amino acyl ester, for treatment of mitochondrial diseases. PCX Int. Appl. WO 2008016554, 2008 Chem. Abstr. 2008, 148, 222003. 

Gao-Feng Liu YL, Tan C-P, Ji L-N, Mao Z-W. Antitumor properties and mechanisms of mitochondria-targeted Ag(I) and Au(I) complexes containing N-heterocyclic carbenes derived from cyclophanes. Metallomics. 2014 6 1460-1468. 

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