Ageing
1
ROS
2
GSH
GSSG
EGSSG/2GSH
Trx – ASK 1
Trx + ASK 1
3
SS
SH SH
4
MAPK cascade
5
6
8
Cytochrome c
BAX
Ca++
BCL
12
7
9
11
13
Metacaspases
SH SH
10
Metacaspases
SS
Death
Annex 1. Proposed mechanisms of programmed cell death.
Reactive oxygen species (ROS) generated during ageing [step 1] cause fluctuations in
cellular redox environment. Glutathione (GSH) is involved in ROS scavenging, but if it is
not re-reduced, glutathione disulfide (GSSG) accumulates and increases glutathione halfcell reduction potential, EGSSG/2GSH [2]. The cell enters the initiation phase of PCD. The
apoptosis signal-regulating kinase (ASK) 1 is split from thioredoxin (Trx) [3] and enters
[4] the MAPK (mitogen activated protein kinase) cascade. In the effector phase, BAXand BCL-like genes are up- and down-regulated [5], respectively, and induce [6] that
cytochrome c leaves [7] the mitochondrion and moves to the endoplasmic reticulum (ER).
BAX and BCL genes have not yet been identified in plants, but a BCL inhibitor gene
exists in both plants and animals that is an ancient cell death suppressor. We therefore use
the terms BAX and BCL-like genes to point out that the pathway may follow a similar
pattern in plants as in animals. In step 8, the ER releases Ca++ which enters the
mitochondrion that then [9] releases more cytochrome c. We suggest that the process is
reversible, but if EGSSG/2GSH is greater than 50-70 mV, metabolic imbalances become
irreversible and the cell enters the execution phase of PCD. High cytochrome c
concentrations in the cytoplasm activate metacaspases [10], a group of cysteine proteases.
These presumably have the same function as caspases in animal cells to break down
structural proteins in the cytoskeleton and nuclear proteins such as DNA repair enzymes,
and to activate DNAses [11], which then [12] cleave DNA, preventing recovery [13].
Further direct damage by ROS to proteins and lipids (project 3.5.1), the involvement of
other antioxidants to scavenge ROS, other death triggers and glutathionylation of proteins
are not considered.
Copyright: Elsevier (Taken from Kranner et al. 2006. Free Radic Biol Med 40, 21552165).
401290168 / Au GF / 28 June 2005 / page 1 of 1