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 voltage-
dependent 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