Impact of Antioxidants on Cardiolipin Oxidation in Liposomes: Why Mitochondrial Cardiolipin Serves as an Apoptotic Signal?
Molecules of mitochondrial cardiolipin (CL) get selectively oxidized upon oxidative stress, which triggers the intrinsic apoptotic pathway. In a chemical model most closely resembling the mitochondrial membrane-liposomes of pure bovine heart CL-we compared ubiquinol-10, ubiquinol-6, and alpha-tocopherol, the most widespread naturally occurring antioxidants, with man-made, quinol-based amphiphilic antioxidants. Lipid peroxidation was induced by addition of an azo initiator in the absence and presence of diverse antioxidants, respectively. The kinetics of CL oxidation was monitored via formation of conjugated dienes at 234 nm. We found that natural ubiquinols and ubiquinol-based amphiphilic antioxidants were equally efficient in protecting CL liposomes from peroxidation; the chromanol-based antioxidants, including alpha-tocopherol, were 2-3 times less efficient. Amphiphilic antioxidants, but not natural ubiquinols and alpha-tocopherol, were able, additionally, to protect the CL bilayer from oxidation by acting from the water phase. We suggest that the previously reported therapeutic efficiency of mitochondrially targeted amphiphilic antioxidants is owing to their ability to protect those CL molecules that are inaccessible to natural hydrophobic antioxidants, being trapped within respiratory supercomplexes. The high susceptibility of such occluded CL molecules to oxidation may have prompted their recruitment as apoptotic signaling molecules by nature.
School of Physics, University of Osnabrueck, 49069 Osnabrueck, Germany; School of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119991, Russia.
Alexey V
AV
Lokhmatikov
School of Physics, University of Osnabrueck, 49069 Osnabrueck, Germany.
Natalia
N
Voskoboynikova
A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia; A.N. Frumkin Institute of Physical Chemistry and Electrochemistry of the Russian Academy of Sciences, Leninsky Prospect 31, Moscow 119991, Russia.
Dmitry A
DA
Cherepanov
Institute of Mitoengineering, Lomonosov Moscow State University, Moscow 119991, Russia.
Maxim V
MV
Skulachev
School of Physics, University of Osnabrueck, 49069 Osnabrueck, Germany.
Heinz-Jürgen
HJ
Steinhoff
School of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119991, Russia; A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia.
Vladimir P
VP
Skulachev
School of Physics, University of Osnabrueck, 49069 Osnabrueck, Germany; School of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119991, Russia; A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia.
Armen Y
AY
Mulkidjanian
D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002308:Cardiolipins / Q000737:chemistry* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008081:Liposomes; D008929:Mitochondria, Heart / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051336:Mitochondrial Membranes / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008956:Models, Chemical; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013501:Surface-Active Agents / Q000737:chemistry* / Q000494:pharmacology; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000737:chemistry* / Q000494:pharmacology
D000975:Antioxidants; D002308:Cardiolipins; D008081:Liposomes; D013501:Surface-Active Agents; D014451:Ubiquinone; D024502:alpha-Tocopherol; C003741:ubiquinol