Mitochondrial targeting of electron scavenging antioxidants: Regulation of selective oxidation vs random chain reactions

Valerian E. Kagan, Peter Wipf, Detcho Stoyanovsky, Joel S. Greenberger, Grigory Borisenko, Natalia A. Belikova, Naveena Yanamala, Alejandro K. Samhan Arias, Muhammad A. Tungekar, Jianfei Jiang, Yulia Y. Tyurina, Jing Ji, Judith Klein-Seetharaman, Bruce R. Pitt, Anna A. Shvedova, Hülya Bayir

Research output: Contribution to journalReview articlepeer-review

91 Scopus citations

Abstract

Effective regulation of highly compartmentalized production of reactive oxygen species and peroxidation reactions in mitochondria requires targeting of small molecule antioxidants and antioxidant enzymes into the organelles. This review describes recently developed approaches to mitochondrial targeting of small biologically active molecules based on: (i) preferential accumulation in mitochondria because of their hydrophobicity and positive charge (hydrophobic cations), (ii) binding with high affinity to an intra-mitochondrial constituent, and (iii) metabolic conversions by specific mitochondrial enzymes to reveal an active entity. In addition, targeted delivery of antioxidant enzymes via expression of leader sequences directing the proteins into mitochondria is considered. Examples of successful antioxidant and anti-apoptotic protection based on the ability of targeted cargoes to inhibit cytochrome c-catalyzed peroxidation of a mitochondria-specific phospholipid cardiolipin, in vitro and in vivo are presented. Particular emphasis is placed on the employment of triphenylphosphonium- and hemi-gramicidin S-moieties as two effective vehicles for mitochondrial delivery of antioxidants.

Original languageEnglish (US)
Pages (from-to)1375-1385
Number of pages11
JournalAdvanced Drug Delivery Reviews
Volume61
Issue number14
DOIs
StatePublished - Nov 30 2009
Externally publishedYes

Keywords

  • Apoptosis
  • Cardiolipin
  • Cytochrome c
  • Gramicidin S-conjugates
  • Mitochondria
  • MnSOD
  • Nitroxides
  • Peroxidation
  • Triphenylphosphonium

ASJC Scopus subject areas

  • Pharmaceutical Science

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