title: How do reactive oxygen species and calcium trigger mitochondrial membrane permeabilisation?
abstract: BACKGROUND
  Mitochondrial membrane permeabilisation (MMP) is classically considered as a point of no return in several forms of cell death and is involved in numerous diseases such as cancer, neurodegenerative disorders or ischemia/reperfusion injuries. Many studies established that reactive oxygen species (ROS) and Ca(2+) were the prominent inducers of MMP. However, the mechanisms connecting ROS and Ca(2+) to the players of MMP are still a matter of debate.
  
  
  METHODS
  The aim of this review is to summarise the various studies related to the mechanisms of ROS- and Ca(2+)-induced MMP. Several lines of evidence suggest that ROS and Ca(2+) cooperate to induce MMP but the molecular details of the ROS-Ca(2+)-MMP network remain controversial. We then discuss recent data depicting this topic.
  
  
  CONCLUSIONS
  Cytotoxic stimuli may be transduced within the cell by ROS and Ca(2+) increases. In most models, Ca(2+) and ROS can cooperate to induce MMP. Moreover, several data suggest that MMP increases mitochondrial Ca(2+) and ROS which therefore amplify the cytotoxic signal. Intriguingly, many reports have identified players of MMP as direct ROS targets. On the contrary, direct targets of Ca(2+) remain elusive. At the same time, the mechanisms by which mitochondrial Ca(2+) overload induces ROS generation are well documented. Upon these observations, we hypothesise that Ca(2+) cannot directly induce MMP and requires ROS production as a mandatory step.
  
  
  CONCLUSIONS
  Given the importance of Ca(2+)- and ROS-induced MMP in diseases, we expect that a better understanding of this process will lead to the development of novel therapies.
authors.affiliation: Laboratory of Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium. Electronic address: nicolas.tajeddine@uclouvain.be.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tajeddine
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D051336:Mitochondrial Membranes / Q000378:metabolism*; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D002118:Calcium
keywords: Apoptosis; Calcium; Intrinsic pathway; Mitochondria; Mitochondrial permeabilisation; Reactive oxygen species