20.8 How Do Mitochondria Mediate Apoptosis? Mitochondria not only are the home of the TCA cycle and oxidative phosphorylation but also are a crossroads for several cell signaling pathways. Mitochondria take up Ca2 ions released from the endoplasmic reticulum, thus helping control intracellular Ca 2 signals. They produce reactive oxygen species (ROS) that play signaling roles in cells, although ROS can also cause cellular damage. Mitochondria also participate in the programmed death of cells, a process known as apoptosis (the second “p” is silent in this word). Apoptosis is a mechanism through which certain cells are eliminated from higher organisms. It is central to the development and homeostasis of multicellular organisms, and it is the route by which unwanted or harmful cells are eliminated. Under normal circumstances, apoptosis is suppressed through compartmentation of the involved activators and enzymes. Mitochondria play a major role in this subcellular partitioning of the apoptotic activator molecules. One such activator is cytochrome c, which normally resides in the intermembrane space, bound tightly to a lipid chain of cardiolipin in the membrane (Figure 20.33). A variety of triggering agents, including Ca2, ROS, certain lipid molecules, and certain protein kinases, can induce the opening of pores in the mitochondrial membrane. For example, using hydrogen peroxide as a substrate, cytochrome c can oxidize its bound cardiolipin chain, releasing itself from the membrane. When the outer membrane is made permeable by other apoptotic signals, cytochrome c can enter the cytosol. Permeabilization events, which occur at points where outer and inner mitochondrial membranes are in contact, involve association of the ATP–ADP translocase in the inner membrane and the voltagedependent anion channel (VDAC) in the outer membrane. This interaction leads to the opening of protein-permeable pores. Cytochrome c, as well as several other proteins, can pass through these pores
