Biology Reference
In-Depth Information
1994; Wyllie et al., 1980). Apoptosis can be triggered by a wide variety of
stimuli, such as deprivation of growth factors, g-irradiation, oxygen free radical
(OFR) production, receptor-ligand interaction, and inhibition of protein kin-
ases. Each stimulus activates its own ``private'' pathway, which is thought to
converge into one or a few central mechanism, the ``common pathway,'' lead-
ing to the classical morphological and biochemical changes found in the cell
dying through apoptosis (Golstein, 1997; Hetts, 1998).
The phenomenon of apoptosis has received unprecedented attention in the
past decade. Recently, there has been persistent and growing interest in the role
of mitochondria during the apoptotic phenomena that occur in several physio-
logical and pathological conditions, including infection by HIV. Initially, the
focus was on the possible role of these organelles in supplying the energy (in
the form of adenosine triphoshate [ATP]) required for such processes to occur
( Richter et al., 1996). In the mitochondrial respiratory chain, the energy re-
leased by oxidation reactions is stored as an electrochemical gradient generated
by the active extrusion of protons from the mitochondrial matrix to the cytosol.
Such a gradient consists of two components: a transmembrane electrical po-
tential of about 180±200 mV, negative inside, and a proton gradient of about
1 pH unit. This energy drives the synthesis of ATP, which is exported into the
cytoplasm and then used, so that mitochondria are, in fact, the main power
stations for aerobic life.
Only recently have scientists understood that these organelles are able to
play two completely opposite roles, determining life or death for the cell. Not
only are they of crucial importance for the generation of intracellular energy,
but they are also capable of generating or amplifying signals that ultimately
lead to programmed cell death/apoptosis. According to a very recent view, it
seems likely that mitochondria possess an autonomic system that allows them
to be degraded when irreversibly damaged, thus committing a sort of suicide,
called ``mitoptosis'' by analogy with apoptosis (Skulachev, 1998, 2000). Mas-
sive mitoptosis resulting from a massive stimulus such as, for example, that
provided by large amounts of reactive oxygen species ( ROS), which, however,
are mostly produced in mitochondria (Skulachev, 1996), can result in apoptosis
because of the release of apoptogenic proteins such as cytochrome c (cyt c)
or the apoptosis-inducing factor (AIF ) that are normally present within the
organelle.
Even before the identi®cation of cyt c and AIF, a crucial role for this or-
ganelle during apoptosis was postulated because of the observation that the
antiapoptotic protein Bcl-2 is present in the outer mitochondrial membrane (de
Jong et al., 1994; Monaghan et al., 1992). Indeed, it was found that either Bcl-2
protein or other members of the same family are preferentially located at the
contact sites where the inner and outer membranes come into close apposition
(de Jong et al., 1994), near to proteaceous structures that form pores in the in-
ner mitochondrial membrane. Such pores are referred to as mitochondrial
``megachannels''or permeability transition pores (Zoratti and Szab
Á
, 1995). The
opening of these pores allows for the free distribution of solutes <1500 Da and
