The Many Shapes of Mitochondrial Death

GM Cereghetti and L Scorrano

Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy

Mitochondria integrate apoptotic signalling by releasing subcellular sites and equal division of the mitochondrial cytochrome c and other proapoptotic cofactors needed for progeny between the two daughter cells during activation of effector caspases. Previously overlooked mor- mitosis (Shaw and Nunnari, 2002). At the same time, phological changes,mitochondrial fragmentation and during the early steps of cell death, mitochondria undergo cristae remodelling,emerged as subroutines of the mito- dramatic structural changes (fragmentation of the chondrial programme of apoptosis in mammalian cells,as reticulum and remodelling of the cristae) that are well as in developmental cell death of Caenorhabditis required to insure progression of the apoptotic cascade elegans. Mitochondrial morphology results from fusion (Scorrano, 2005). and fission processes,controlled by a growing set of The search for the molecular mechanisms involved in ‘mitochondria-shaping’ proteins. Their levels and function the structural modification of mitochondria during appear to influence mitochondrial pathways of cell death, apoptosis has raised interest on the molecular mechan- but mechanisms are largely unknown. An emerging model isms working behind the scenes of mitochondrial shape implicates different signals converging on mitochondria- changes, eventually leading to increased knowledge on shaping proteins to activate or deactivate them during the proteins controlling the morphology of this orga- apoptosis. In turn,these proteins can orchestrate changes nelle. Several crucial questions remain open: what is the in mitochondrial shape to insure cytochrome c release and relative role of mitochondrial shape changes in the progression of the apoptotic cascade. These therefore apoptotic pathways? Are these epiphenomena of the appear an appealing novel therapeutic target to modulate many functional changes occurring at the mitochondrial cell death in cancer. level during cell death or are these really required for Oncogene (2006) 25, 4717–4724. doi:10.1038/sj.onc.1209605 apoptosis to proceed? What is their relationship with known players of the mitochondrial pathways of Keywords: mitochondria; cytochrome c release; fusion; apoptosis, such as Bcl-2 family members? Are all these fission; cristae; apoptosis changes somehow coordinated and if yes, how? Can we identify signals that recruit these mitochondria-shaping proteins in the apoptotic cascade? Recent evidences have started to clarifying some of these questions.

Introduction

Mitochondria are the site of the tricarboxylic acid The many shapes of mitochondria cycle and oxidative phosphorylation, the last steps of cellular respiration producing most energy required by In the last years, some of the principal regulators of the cell. The number of mitochondrial units in a mitochondrial shape have been identified and character- particular cell type is determined by its energetic demand, ized. Pioneer work in Saccharomyces cerevisiae has been so for example, hepatocytes possess thousands of followed by the identification of orthologues in mam- mitochondria, whereas erythrocytes have lost all of them malian systems (Yaffe, 1999). Both fusion and fission as their energy production relies exclusively on glycolysis. processes are controlled by evolutionarily conserved These ‘mitochondrial units’ have a major axis of 2–5 mm, large GTPases belonging to the dynamin family. Dy- namins are large, ubiquitous mechanoenzymes that use as observed in classical electron micrographs of isolated 0 mitochondria. In the cytosol of a living cell, these display the free energy generated by guanine 5 -triphosphate an elongated, t