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Targeting Mitochondria: The Road to Mitochondriotropic Antioxidants and Beyond

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Mitochondrial Biology and Experimental Therapeutics

Abstract

Mitochondria are sub-cellular organelles that play a central role in energy metabolism, being these organelles currently recognized as one important target for new drug discovery programs addressed to find innovative therapeutic solutions for diverse pathologic events, such as cancer, cardiovascular, and neurological diseases. Although attractive, the success of the strategies developed so far has been hampered by several challenges and limitations, and until now the Food and Drug Administration (FDA) has not approved a drug for mitochondrial therapy. Currently, the most effective strategy to deliver drugs specifically to mitochondria is the covalent link of a lipophilic cation, namely triphenylphosphonium (TPP), to a pharmacophore of interest. Within this framework two mitochondriotropic antioxidants (MitoQ and SkQ1) have entered in human clinical trials as a therapeutic solution for oxidative-stress related diseases. In this chapter, the efforts done so far to target small-molecule antioxidants to mitochondria as potential therapeutics or diagnostic tools have been reviewed. Although TPP cation has been the most extensively used mitochondrial-targeting cation, there are still controversies surrounding this approach, namely related with its intrinsic toxicity. Consequently, efforts must be done in finding new cation carriers, and to guarantee that the cargo does indeed access the mitochondrial matrix and does not merely associate with the mitochondrial membranes. Moreover, in vivo biodistribution, pharmacokinetics and long-term toxic effects studies to provide accurate information about efficacy and toxicity are still an emergent issue to make available the translation from bench to bedside.

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Abbreviations

2-DG:

2-Deoxy-D-glucose

CoQ:

Co-enzyme Q

EPR:

Electron paramagnetic resonance

ETC:

Electron transport chain

FAD:

Flavin adenine dinucleotide

GPx:

Glutahione peroxidase

GSH:

Reduced glutathione

H2O2 :

Hydrogen peroxide

H2S:

Hydrogen sulfide

MIM:

Mitochondrial inner membrane

mPTP:

Mitochondrial permeability transition pore

mtDNA:

Mitochondrial DNA

ONOO− :

Peroxynitrite

OXPHOS:

Oxidative phosphorylation

Prx3:

Peroxiredoxine 3

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

TCA:

Tricarboxylic acid

TP:

Two-photon

TPP or PPh3 :

Triphenylphosphonium

ΔΨm:

Mitochondrial membrane potential

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Acknowledgements

This work was funded by FEDER funds through the Operational Programme Competitiveness Factors—COMPETE and national funds by FCT—Foundation for Science and Technology under research grants PTDC/DTP-FTO/2433/2014, POCI-01-0145-FEDER-016659, POCI-01-0145-FEDER-007440, POCI-01-0145-FEDER-006980, and NORTE-01-0145-FEDER-000028. R. Amorim (PTDC/DTP-FTO/2433/2014), S. Benfeito (SFRH/BD/99189/2013), J. Teixeira (NORTE-01-0145-FEDER-000028) and F. Cagide (NORTE-01-0145-FEDER-000028) grants are supported by the European Regional Development Fund (ERDF) through the COMPETE 2020—Operational Programme for Competitiveness and Internationalisation and Portuguese national funds.

Declaration of Interest 

The authors declare no competing financial interest. PJO and FB are co-founders of the CNC spin-off company MitoTAG.

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  1. CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal

    Ricardo Amorim, Sofia Benfeito, José Teixeira, Fernando Cagide & Fernanda Borges

  2. CNC – Center for Neuroscience and Cell Biology, University of Coimbra, Cantanhede, Portugal

    Ricardo Amorim, José Teixeira & Paulo J. Oliveira

Authors
  1. Ricardo Amorim
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  2. Sofia Benfeito
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  3. José Teixeira
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  4. Fernando Cagide
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  5. Paulo J. Oliveira
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  6. Fernanda Borges
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Corresponding author

Correspondence to Fernanda Borges .

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Editors and Affiliations

  1. CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Paulo J. Oliveira

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Amorim, R., Benfeito, S., Teixeira, J., Cagide, F., Oliveira, P.J., Borges, F. (2018). Targeting Mitochondria: The Road to Mitochondriotropic Antioxidants and Beyond. In: Oliveira, P. (eds) Mitochondrial Biology and Experimental Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-73344-9_16

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