Apoptosis and mitochondria

Abstract

Among the various recognized forms of cell death that include necrosis and autophagy, apoptosis or programmed cell death is evolutionarily conserved, highly organized, and characterized by unique nuclear changes, chromatin shrinkage, DNA fragmentation, membrane blebbing, and formation of apoptotic bodies that contain components of the dying cell. Apoptosis is a crucial component of life that eliminates unwanted cells and is vital for embryonic development, homeostasis, and immune defense. Dysregulation of apoptosis underlies many pathophysiological states and diseases. The key mediators of apoptotic cell death are cysteine proteases, called caspases, that work in a coordinated cascade to cleave key substrates and dismantle the cell [1]. The caspase cascade involves initiator caspases and executioner caspases that can be activated in different ways by different apoptotic stimuli. While changes in nuclei are characteristic in apoptotic cell death, other subcellular organelles are also involved such as endoplasmic reticulum, lysosomes, and, particularly, mitochondria. Moreover, although caspases are crucial in apoptosis, similar morphologic changes can be produced in a caspase-independent fashion. In vertebrates, caspase-dependent apoptosis occurs through two main pathways, the extrinsic pathway and the intrinsic pathway (Fig. 29.1). The extrinsic pathway is initiated upon the binding of an extracellular ligand to transmembrane death receptors of the TNF superfamily (see below), which leads to the assembly of the death-inducing signaling complex (DISC). The DISC then activates an initiator caspase, which triggers the enzymatic cascade that leads to apoptotic death. The intrinsic pathway, also known as the mitochondrial pathway, is activated by stimuli that lead to the permeabilization of the outer mitochondrial membrane (OMM) and the subsequent release of proteins from the mitochondrial intermembrane space (IMS), which initiate or regulate caspase activation, such as cytochrome c. Cytochrome c normally resides within the cristae of the inner mitochondrial membrane (IMM) and is effectively sequestered by narrow cristae junctions. Within the IMM, cytochrome c participates in the mitochondrial electron-transport chain, using its heme group as a redox intermediate to shuttle electrons between complex III and complex IV. However, when the cell detects an apoptotic stimulus, such as DNA damage, or metabolic stress, the intrinsic apoptotic pathway is triggered and mitochondrial cytochrome c is released into the cytosol. This process is thought to occur in two phases, first the mobilization of cytochrome c and then its translocation through permeabilized OMM. In addition to cytochrome c, other IMS proteins are mobilized and released into the cytosol where they are engaged in a strategic battle to promote or counteract caspase activation and hence cell death. © 2010 Springer-Verlag Berlin Heidelberg.