title: Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Pharmacology, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: A V
authors.initials: AV
authors.lastname: Birk
authors.forename: W M
authors.initials: WM
authors.lastname: Chao
authors.forename: C
authors.initials: C
authors.lastname: Bracken
authors.forename: J D
authors.initials: JD
authors.lastname: Warren
authors.forename: H H
authors.initials: HH
authors.lastname: Szeto
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D002308:Cardiolipins / Q000187:drug effects* / Q000378:metabolism; D045304:Cytochromes c / Q000187:drug effects* / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D008081:Liposomes / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats
chemical_list: D002308:Cardiolipins; D008081:Liposomes; D009842:Oligopeptides; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D000255:Adenosine Triphosphate; D045304:Cytochromes c
keywords: ATP synthesis; Bendavia®; SS peptides; SS-31; Szeto-Schiller peptides; cardiolipin; cardiolipin peroxidation; cyt c; electron transport; mitochondria; mitochondria-targeted peptides