Fis1, Bap31 and the kiss of death between mitochondria and endoplasmic reticulum

Abstract

Dynamic structural and functional liaisons between mitochondria and the endoplasmic reticulum (ER) support a wide range of cell functions, including the ability of the cell to kill itself by apoptosis. A new study in this issue of The EMBO Journal sheds light on how these interactions regulate Bax/Bak‐driven cell death within the complex milieu of the cell, suggesting that mitochondria–ER dynamics can involve an unanticipated two‐way communication in cell death, from mitochondria to ER and back again. Much of our knowledge on apoptosis induction in higher organisms, which revolves around mitochondria and proapoptotic Bcl‐2 family members such as Bax or Bak, has derived from reconstitution studies using biochemical and genetically defined systems. These studies revealed step‐wise activation of Bax/Bak in the mitochondrial outer membrane by activator BH3‐only proteins, regulated by prosurvival Bcl‐2 family proteins as well as by sensitizing BH3‐only proteins. In the complex environment of the intact cell, however, where the potential for competing reactions is enormous, the question of efficiencies and specificities takes precedence. As a consequence, there exists a large array of supporting players to ensure rapid and orderly cell demise by the Bax/Bak mechanism. Not surprisingly, many of these supporting roles involve mitochondrial biology—in particular, mitochondrial fusion/fission dynamics as well as the close physical and functional relationship of the mitochondrion with …