Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Academic Article uri icon

Overview

MeSH

  • Animals
  • Electron Transport
  • Liposomes
  • Mitochondrial Membranes
  • Oxidation-Reduction
  • Oxygen Consumption
  • Rats

MeSH Major

  • Adenosine Triphosphate
  • Cardiolipins
  • Cytochromes c
  • Mitochondria
  • Oligopeptides

abstract

  • Cardiolipin plays an important role in mitochondrial respiration and cardiolipin peroxidation is associated with age-related diseases. Hydrophobic interactions between cytochrome c and cardiolipin converts cytochrome c from an electron carrier to a peroxidase. In addition to cardiolipin peroxidation, this impedes electron flux and inhibits mitochondrial ATP synthesis. SS-31 (D-Arg-dimethylTyr-Lys-Phe-NH2 ) selectively binds to cardiolipin and inhibits cytochrome c peroxidase activity. Here, we examined whether SS-31 also protected the electron carrier function of cytochrome c. Interactions of SS-31 with cardiolipin were studied using liposomes and bicelles containing phosphatidylcholine alone or with cardiolipin. Structural interactions were assessed by fluorescence spectroscopy, turbidity and nuclear magnetic resonance. Effects of cardiolipin on electron transfer kinetics of cytochrome c were determined by cytochrome c reduction in vitro and oxygen consumption using mitoplasts, frozen and fresh mitochondria. SS-31 interacted only with liposomes and bicelles containing cardiolipin in about 1:1 ratio. NMR studies demonstrated that the aromatic residues of SS-31 penetrated deep into cardiolipin-containing bilayers. SS-31 restored cytochrome c reduction and mitochondrial oxygen consumption in the presence of added cardiolipin. In fresh mitochondria, SS-31 increased state 3 respiration and efficiency of ATP synthesis. SS-31 selectively targeted cardiolipin and modulated its interaction with cytochrome c. SS-31 inhibited the cytochrome c/cardiolipin complex peroxidase activity while protecting its ability to serve as an electron carrier, thus optimizing mitochondrial electron transport and ATP synthesis. This novel class of cardiolipin therapeutics has the potential to restore mitochondrial bioenergetics for treatment of numerous age-related diseases. © 2013 The British Pharmacological Society.

publication date

  • April 2014

has subject area

  • Adenosine Triphosphate
  • Animals
  • Cardiolipins
  • Cytochromes c
  • Electron Transport
  • Liposomes
  • Mitochondria
  • Mitochondrial Membranes
  • Oligopeptides
  • Oxidation-Reduction
  • Oxygen Consumption
  • Rats

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3976619

Digital Object Identifier (DOI)

  • 10.1111/bph.12468

PubMed ID

  • 24134698

Additional Document Info

start page

  • 2017

end page

  • 2028

volume

  • 171

number

  • 8