428 IRON-CONTAINING PROTEINS AND ENZYMES
diseases, and neurodegenerative disorders may occur. Apoptopic events are
controlled by cysteine proteases known as caspases. In mammals, caspase
activity may be initiated through a cytochrome c pathway. The pathway begins
when cytochrome c is released from mitochondria, initiating a series of reac-
tions resulting in caspase activation and eventual cell death. In a recent review,
Jiang and Wang focus on regulation of the pathway, its connection to physiol-
ogy and disease, and potential therapeutics resulting from enhanced under-
standing of the apoptosis process.^104 Figure 1 of reference 104 shows the
pathway controlling cytochrome c ’ s role in cell death. The pathway requires
participation of deoxy ATP (dATP) to induce activation of aspase - 3, a homolog
of caspase - 9. Apaf - 1, a binding partner of dATP, is also involved in pathway
regulation. The oncogene BCL - 2 family ’ s role in the process is to prohibit
cytochrome c release from the mitochondria. These facts are gathered from
much research involving knockout animals — animals lacking the Apaf - 1,
caspase - 9, and caspase - 3 genes. The animals exhibited severe defects in central
nervous system (CNS) development, indicating that the cytochrome c -
mediated caspase activation pathway has an essential role in CNS develop-
ment. The cytochrome c - mediated caspase activation pathway is also involved
in amplifi cation processes in cells known as type II cells. Certain cancers origi-
nate in type II cells. It is believed that therapeutics could be developed that
target the cytochrome c - mediated caspase activation pathway pathway in
synergism with attacks on other cancer - causing pathways. Why does the cyto-
chrome c - mediated caspase activation pathway have its starting point(s) within
the mitochondria? The reference 104 authors believe that the pathway can be
isolated within the mitochondria and only perform its killing function when
released during apoptosis.
The biochemistry of how cytochrome c - mediated caspase activation pathway
triggers apoptosis is complex. Selected problems include: (1) formation of the
so - called apoptosome with cytochrome c and it other necessary partners (see
Figure 3 of reference 104 ); (2) inhibition of the apoptosome ’ s activity — one
example being inhibition with so - called heat shock proteins (HSP); and (3)
combination of the apoptosome with other proteins to trigger oncogenes
(cancer - causing genes). Questions that remain to be answered include the fol-
lowing: (1) Mechanistically, how do BCL - 2 family proteins control release of
cytochrome c and other proteins from the mitochondria? (2) How is the cyto-
chrome c - mediated caspase activation pathway activated? and (3) How can
the pathway, a promising cancer therapy target, be used to generate clinically
effective anti - cancer therapies?
Hancock, Desikan, and Neill have studied the redox status of cytochrome
c in relation to apoptosis progression.^136 First, they fi nd that the redox status
of cytochrome c, as well as the structure of cytochrome c, can change in the
presence of reactive oxygen species (ROS, superoxide radical anion O⋅− 2 or
H 2 O 2 ) or reduced glutathione (GSH; see Figure 7.37 ). These authors believe
that high levels of cytoplasmic GSH will maintain cytochrome c in its inactive
Fe(II) state. In the presence of H 2 O 2 , GSH concentrations may drop, cyto-