Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis

AV Birk, WM Chao, C Bracken… - British journal of …, 2014 - Wiley Online Library
British journal of pharmacology, 2014Wiley Online Library
Background and Purpose 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‐A rg‐dimethyl T yr‐L ys‐P he‐NH2)
selectively binds to cardiolipin and inhibits cytochrome c peroxidase activity. Here, we …
Background and Purpose
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.
Experimental Approach
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.
Key Results
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.
Conclusions and Implications
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.
Linked Articles
This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue‐8
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