mitocHonDria’s role in cell DeatH
Found in all cells, mitochondria provide cellular energy in their role as the
body’s power generators. In addition, mitochondria are intricately involved in a
process called apoptosis, or programmed cell death, which is the body’s normal
method of disposing of damaged, unwanted or unneeded cells. Apoptosis can
be defined as a cell death process in which activation of catabolic processes and
enzymes occurs prior to the bursting of the cell (cytolysis), thereby facilitating
the recognition, uptake, and digestion of the apoptotic cell by dying neighboring
cells. Cytolysis occurs in a hypotonic environment, where due to the lower osmotic
pressure, water diffuses into the cell until there is more solutes within the cell. If
too much water enters the cell will eventually burst, releasing cell contents.
The central role of mitochondria in neurodegenerative disorders has become
apparent. Mitochondria appear to be most susceptible in glutathione-depleted
tissues because of the high flux of oxygen radicals from the mitochondria’s
OxPhos activities. Because the mitochondria assume the bulk of the endogenous
oxygen radical burden, yet are unable to make their own GSH, so they must
import it from the cell cytosol. As oxidative phosphorylation proceeds in the
mitochondria, invariably single electrons escape, leaking out to react with ambient
oxygen and generate oxygen free radicals. An estimated 2-5% of the electrons that
pass through the OxPhos system become free radicals and since OxPhos processes
at least 95 percent of all the oxygen used by the body, this flux of wayward oxygen
free radicals poses a potential toxic risk to the organism.
Mitochondria exhibit major changes in their structure and function during
apoptosis and are now considered major players in the apoptotic process of
mammalian cells. Mitochondria have been implicated in the maintenance of the
calcium (Ca2+) “set-point” in cells, where control of Ca2+ levels plays a significant
role in enzymatic regulation and energy production. Pathological conditions that
result in increased tissue Ca2+ concentrations include ischemia, oxidative stress,
and excito- and neurotoxicity. The subsequent increase in cytoplasmic Ca2+ is
widely considered to be a critical initiating event in the development of damage
in cells destined to die. Apoptotic and necrotic cell damage is always preceded by
an increase in Ca2+. Ca2+ increase in cerebrospinal fluid was noted in connection
with psychotic episodes, so I imagine that acid conditions promote cell death prior
to and during psychosis.
Cell energy production is reduced by excessive free cytosolic Ca2+ leading
to uncoupling of mitochondrial oxidative phosphorylation with consequently
decreased ATP synthesis. The resulting inactivity of ATP-dependent pumps
would lead to membrane depolarization and further exacerbating Ca2+ influx in
self-reinforcing accumulative fashion. The cells then make an effort to restore the
normal cytoplasmic Ca2+ concentration by removing Ca2+ to the extracellular
space and/or uptake into organelles, including mitochondria.
sodium influx into cells causes depolarization and increased Ca2+ levels in the
cells. In depression (down), mood shifts are accompanied by shifts in the amount
of salt and fluid in and around the cells. Depressed patients have consistently