0361293 - BTÚ 2013 RIV US eng J - Článek v odborném periodiku
Dong, L.F. - Jameson, V.J.A. - Tilly, D. - Černý, Jiří - Mahdavian, E. - Marin-Hernandez, A. - Hernandez-Esquivel, L. - Rodriguez-Enriquez, S. - Štursa, Jan - Witting, P.K. - Stantic, B. - Rohlena, Jakub - Truksa, Jaroslav - Klučková, Katarína - Dyason, J.C. - Ledvina, Miroslav - Salvatore, B.A. - Moreno-Sanchez, R. - Coster, M. - Ralph, S.J. - Smith, A.J. - Neužil, Jiří
Mitochondrial targeting of vitamin E succinate enhances its pro-apoptotic and anti-cancer activity via mitochondrial complex.
Journal of Biological Chemistry. Roč. 286, č. 5 (2011), s. 3717-3728. ISSN 0021-9258. E-ISSN 1083-351X
Grant CEP: GA ČR(CZ) GA204/08/0811; GA ČR(CZ) GAP301/10/1937; GA AV ČR(CZ) IAA500520702; GA AV ČR(CZ) KAN200520703; GA AV ČR(CZ) KJB500970904
Výzkumný záměr: CEZ:AV0Z50520701; CEZ:AV0Z4055905
Klíčová slova: Apoptosis induction * proximal ubiquinone-binding site of mitochondrial complex II * reactive oxygen species
Kód oboru RIV: EB - Genetika a molekulární biologie
Impakt faktor: 4.773, rok: 2011 ; AIS: 2.031, rok: 2011
DOI: https://doi.org/10.1074/jbc.M110.186643

Mitochondrially targeted vitamin E succinate (MitoVES) has enhanced pro-apoptotic and anti-cancer activities. It caused apoptosis and generation of ROS in CII-proficient malignant cells but not their CII-dysfunctional counterparts. It inhibited SDH activity of CII with IC50 of 80 mu M and electron transfer from CII to CIII with IC50 of 1.5 mu M. Molecular modeling predicted its succinyl group anchored into the proximal CII ubiquinone (UbQ)-binding site and reduced interaction energies for its serially shorter phytyl chain homologs correlated with their lower effects on apoptosis induction, ROS generation, and SDH activity. Mutation of the UbQ-binding Ser(68) within the proximal site of the CII SDHC subunit suppressed both ROS generation and apoptosis induction by it. We propose that mitochondrial targeting of VES with an 11-carbon chain localizes the agent into an ideal position across the interface of the mitochondrial inner membrane and matrix, optimizing its anti-cancer effect
Trvalý link: http://hdl.handle.net/11104/0198639