Molecular mechanism for the selective impairment of cancer mitochondrial function by a mitochondrially targeted vitamin E analogue
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- 作者：Sara Rodr¨ªguez-Enr¨ªquez ; Luz Hern¨¢ndez-Esquivel ; Alvaro Mar¨ªn-Hern¨¢ndez ; Lan-Feng Dong ; Emmanuel T. Akporiaye ; Jiri Neuzil ; Stephen J. Ralph ; Rafael Moreno-S¨¢nchez
- 关键词：CII ; respiratory complex II ; MitoVES ; triphenylphosphonium tagged vitamin E succinate ; mtDNA ; mitochondrial DNA ; 2-OG ; 2-oxoglutarate ; OxPhos ; oxidative phosphorylation ; Pyr/Mal ; pyruvate ; + ; malate ; RLM ; rat liver mitochondria ; SDH ; succinate deh
- 刊名：Biochimica et Biophysica Acta (BBA)/Bioenergetics
- 出版年：2012
- 出版时间：September, 2012
- 年：2012
- 卷：1817
- 期：9
- 页码：1597-1607
- 全文大小：844 K
文摘
The effects of ¦Á-tocopheryl succinate (¦Á-TOS), ¦Á-tocopheryl acetyl ether (¦Á-TEA) and triphenylphosphonium-tagged vitamin E succinate (mitochondrially targeted vitamin E succinate; MitoVES) on energy-related mitochondrial functions were determined in mitochondria isolated from AS-30D hepatoma and rat liver, bovine heart sub-mitochondrial particles (SMPs), and in rodent and human carcinoma cell lines and rat hepatocytes. In isolated mitochondria, MitoVES stimulated basal respiration and ATP hydrolysis, but inhibited net state 3 (ADP-stimulated) respiration and Ca2 + uptake, by collapsing the membrane potential at low doses (1-10 ¦ÌM). Uncoupled mitochondrial respiration and basal respiration of SMPs were inhibited by the three drugs at concentrations at least one order of magnitude higher and with different efficacy: MitoVES > ¦Á-TEA > ¦Á-TOS. At high doses (> 10 ¦ÌM), the respiratory complex II (CII) was the most sensitive MitoVES target. Acting as an uncoupler at low doses, this agent stimulated total O2 uptake, collapsed ?¦×m, inhibited oxidative phosphorylation and induced ATP depletion in rodent and human cancer cells more potently than in normal rat hepatocytes. These findings revealed that in situ tumor mitochondria are preferred targets of the drug, indicating its clinical relevance.