Mitochondria targeting of nonperoxidizable triphenylphosphonium-conjugated oleic acid protects mouse embryonic cells against apoptosis: role of cardiolipin remodeling.
Tyurina-Y; Tungekar-MA; Jung-M; Tyurin-VA; Stoyanovsky-DA; Kagan-VE
Toxicologist 2012 Mar; 126(Suppl 1):438-439
The early stage of intrinsic apoptosis is characterized by the formation of cardiolipin (CL) /cytochrome c complexes in mitochondria that exhibit a potent peroxidase activity towards polyunsaturated CL. Accumulation of CL oxidation products in mitochondria of apoptotic cells has been found essential for the release of proapoptotic factors into the cytosol. We suggested that integration of mono-unsaturated octadecaenoic acid (C18:1) into CL - via its remodeling pathways in mitochondria - will generate nonoxidizable CL species hence protect cells against apoptosis. We synthesized a nonperoxidizable triphenylphosphonium (TPP) C18:1 ester (TPP-C18:1) and used it for targeted delivery into mitochondria of mouse embryonic cells (MEC). Using oxidative lipidomics analysis we established that pro-apoptotic stimulation with actinomycin D (AcD) was accompanied by selective oxidative consumption of CL molecular species containing polyunsaturated octadecadienoic, eicosatetraenoic, eicosatrienoic, docosahexaenoic and docosapentaenoic acids. Pretreatment of MEC with TPP-C18:1 resulted in: i) significant decrease of CL polyunsaturated molecular species and simultaneous elevation of nonoxidizable CL molecular species containing C18:1 and ii) suppression of AcD induced apoptosis. An inhibitor of long chain acyl-CoA synthase, triacsin C, blocked integration of C18:1 into CL molecules and restored MEC's sensitivity to AcD-induced apoptosis. Thus, metabolic remodeling of CL can be a new strategy in regulation of apoptotic cell death pathway and lead to the development of new preventive and therapeutic approaches against pathological conditions where apoptosis is a major contributor, eg, acute radiation syndrome.
Phospholipids; Oxidative-phosphorylation; Oxidative-processes; Oxidation; Peroxidases; Cytology; Cell-damage; Cell-morphology; Cellular-function; Acids; Esters; Laboratory-animals; Molecular-biology; Cell-metabolism; Radiation; Radiation-injury; Pathology
The Toxicologist. Society of Toxicology 51st Annual Meeting and ToxExpo, March 11-15, 2012, San Francisco, California
University of Pittsburgh at Pittsburgh