文章基本信息

标题：Intramitochondrial calcium regulation by the FHIT gene product sensitizes to apoptosis
本地全文：下载
作者：Alessandro Rimessi ; Saverio Marchi ; Carmen Fotino 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：31
页码：12753-12758
DOI：10.1073/pnas.0906484106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Despite the growing interest in the Fhit tumor suppressor protein, frequently deleted in human cancers, the mechanism of its powerful proapoptotic activity has remained elusive. We here demonstrate that Fhit sensitizes the low-affinity Ca2+ transporters of mitochondria, enhancing Ca2+ uptake into the organelle both in intact and in permabilized cells, and potentiating the effect of apoptotic agents. This effect can be attributed to the fraction of Fhit sorted to mitochondria, as a fully mitochondrial Fhit (a chimeric protein including a mitochondrial targeting sequence) retains the Ca2+ signaling properties of Fhit and the proapoptotic activity of the native protein (whereas the effects on the cell cycle are lost). Thus, the partial sorting of Fhit to mitochondria allows to finely tune the sensitivity of the organelle to the highly pleiomorphic Ca2+ signals, synergizing with apoptotic challenges. This concept, and the identification of the molecular machinery, may provide ways to act on apoptotic cell death and its derangement in cancer.
关键词：calcium signaling ; mitochondria ; oncosopressor ; oxidative stress