Abstract
As mitochondria have an important role as ATP supplier, cellular ROS producer and apoptosis regulator, these organelles are a promising target for pharmacological intervention in the treatment and management of several diseases. Consequently, research on mitochondria-targeted drugs, which exclude other intracellular structures or extracellular processes, is becoming a hot topic. One approach to address the specific targeting is to conjugate bioactive molecules to a lipophilic cation such as the triphenylphosphonium (TPP+). In this chapter, the development of a new antioxidant based on the dietary cinnamic acid—caffeic acid—is described as well as the demonstration of its mitochondriotropic activity.
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References
Yang CS, Landau JM, Huang MT et al (2001) Inhibition of carcinogenesis by dietary polyphenolic compounds. Annu Rev Nutr 21:381–406
Esteves M, Siquet C, Gaspar A et al (2008) Antioxidant versus cytotoxic properties of hydroxycinnamic acid derivatives—a new paradigm in phenolic research. Arch Pharm 341:164–173
Menezes JC, Kamat SP, Cavaleiro JA et al (2011) Synthesis and antioxidant activity of long chain alkyl hydroxycinnamates. Eur J Med Chem 46:773–777
Manach C, Scalbert A, Morand C et al (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79:727–747
Smith RAJ, Hartley RC, Murphy MP (2011) Mitochondria-targeted small molecule therapeutics and probes. Antioxid Redox Signal 15:3021–3038
Teixeira J, Soares P, Benfeito S et al (2012) Rational discovery and development of a mitochondria-targeted antioxidant based on cinnamic acid scaffold. Free Radic Res 46:600–611
Bernardi P, Scorrano L, Colonna R et al (1999) Mitochondria and cell death. Mechanistic aspects and methodological issues. Eur J Biochem 264:687–701
Bonda D, Wang X, Gustaw-Rothenberg K et al (2009) Mitochondrial drugs for Alzheimer disease. Pharmaceuticals 2:287–298
Petersen RB, Nunomura A, Lee HG et al (2007) Signal transduction cascades associated with oxidative stress in Alzheimer’s disease. J Alzheimers Dis 11:143–152
Brookes PS, Yoon Y, Robotham JL et al (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol 287:C817–C833
Manash PK, Rajan TK, Anup MK (2006) Mitochondria—role in different diseases: potential for drug development. CRIPS 7:42–46
Szewczyk A, Wojtczak L (2002) Mitochondria as a pharmacological target. Pharmacol Rev 54:101–127
Prescott DM (1975) Methods in cell biology, 2nd edn. Elsevier, Amsterdam
Oliveira PJ (2011) Mitochondria as a drug target in health and disease. Curr Drug Targets 12:761
Dessolin J, Schuler M, Quinart A et al (2002) Selective targeting of synthetic antioxidants to mitochondria: towards a mitochondrial medicine for neurodegenerative diseases? Eur J Pharmacol 447:155–161
Skulachev VP (2005) How to clean the dirtiest place in the cell: cationic antioxidants as intramitochondrial ROS scavengers. IUBMB Life 57:305–310
Smith RAJ, Porteous CM, Gane AM et al (2003) Delivery of bioactive molecules to mitochondria in vivo. Proc Natl Acad Sci U S A 100:5407–5412
Mitchell P, Moyle J (1969) Estimation of membrane potential and pH difference across the cristae membrane of rat liver mitochondria. Eur J Biochem 7:471–484
Azzone GF, Petronilli V, Zoratti M (1984) ‘Cross-talk’ between redox- and ATP-driven H+ pumps. Biochem Soc Trans 12:414–416
Azzone GF, Pietrobon D, Zoratti M (1984) Determination of the proton electrochemical gradient across biological membranes. Curr Top Bioenerg 13:1–77
Brown GC, Cooper CE (1995) Bioenergetics: a practical approach, 1st edn. Oxford University Press, USA
Ross MF, Kelso GF, Blaikie FH et al (2005) Lipophilic triphenylphosphonium cations as tools in mitochondrial bioenergetics and free radical biology. Biochemistry (Mosc) 70:222–230
Murphy MP, Smith RA (2007) Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu Rev Pharmacol 47:629–656
Murphy MP, Smith RA (2000) Drug delivery to mitochondria: the key to mitochondrial medicine. Adv Drug Deliv Rev 41:235–250
Birnie GD (1972) Subcellular components: preparation and fractionation, 1st edn. Butterworth, UK
Gornall AG, Bardawill CJ, David MM (1949) Determination of serum proteins by means of the biuret reaction. J Biol Chem 177:751–766
Kamo N, Kobatake Y (1986) Changes of surface and membrane potentials in biomembranes. Methods Enzymol 125:46–58
Kamo N, Muratsugu M, Hongoh R et al (1979) Membrane potential of mitochondria measured with an electrode sensitive to tetraphenyl phosphonium and relationship between proton electrochemical potential and phosphorylation potential in steady state. J Membr Biol 49:105–121
Acknowledgements
This work was supported by the Foundation for Science and Technology (FCT), Portugal (PEst-C/QUI/UI0081/2013), (PEst-C/SAU/LA0001/2013-2014), PTDC/SAU-TOX/110952/2009. J. Teixeira (SFRH/BD/79658/2011) acknowledges the FCT grant.
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Teixeira, J., Soares, P., Benfeito, S., Murphy, M.P., Oliveira, P.J., Borges, F. (2015). Bridging the Gap Between Nature and Antioxidant Setbacks: Delivering Caffeic Acid to Mitochondria. In: Weissig, V., Edeas, M. (eds) Mitochondrial Medicine. Methods in Molecular Biology, vol 1265. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2288-8_6
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DOI: https://doi.org/10.1007/978-1-4939-2288-8_6
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