25
System biolog
y
The criteria of life and aging from a molecular viewpoint…
ing the process of differentiation to the mature blood cell. An
anucleated reticulocyte containing reticular accumulations of
remnant RNA, ribosomes and mitochondria
is an intermediate
stage. As compared with nucleated cells whose proteome has
about 20 000 – 30 000 proteins, erythrocytes contain about
350 various membrane proteins and 250 soluble cytoplasmic
proteins [9, 10].
Erythrocyte life-span, measured using cohort methods (in-
corporation of isotope into newly synthesized blood cells) and
random-label methods is about 120 days [11]. Erythrocytes
preserve automatic metabolic equilibrium (steady state) to assure
indispensable appropriateness of ionic milieu and oxidation-
reduction potential. The abrupt, not smooth termination of life of
the red blood cell implies the existence of
a mechanism which
deines the end of the function. The maintenance of internal stabil
-
ity despite dramatic changes in the external environment having
impact on the cell in the organism indicates that automaticity is
its reliable feature.
Erythrocytes perform hard work by counteracting environ-
mental conditions while traveling between the respiratory system
and tissues. Human red blood cells every minute on average
enter pulmonary capillaries where
they unload carbon dioxide
and protons (the Haldane effect). The oxygen-rich environment of
the lung and transport of oxygen bound to hemoglobin increase
exposure to oxidative stress [12]. Hemoglobin autooxidation
reactions are the main source of active superoxide anion radicals
in the erythrocyte [13]. In these reactions oxyHb transforms into
MetHb releasing superoxide anion radical. It appears that in
oxyhemoglobin Hb-Fe
++
- O
2
is in equilibrium with Hb-Fe
+++
- O
2
-
.
The latter form may undergo spontaneous dissociation. About
3% of oxyhemoglobin per day is dissociated in this way under
physiological conditions. Superoxide anion radical may undergo
further reaction to obtain active derivatives (Fig. 2). The activity
of mainly enzymatic antioxidant systems decreases the amount
of metHb to about 1% [14].
Fig. 2.
The cascade of hemoglobin autooxidative reactions.
The abbreviations used are: SOD, superoxide dismutase;
CAT, catalase
Additionally, certain xenobiotics and
infections increase expo-
sure to reactive oxygen species. They produce hydrogen perox
-
ide, which in the presence of reduced glutathione is neutralized
by glutathione peroxidase. One of the serious consequences of
the action of oxidative factors on the erythrocyte is the formation
of denaturated hemoglobin deposits, so-called Heinz bodies
[11]. Hemichrome and hemin, generated during hemoglobin
denaturation, may bind to
the erythrocyte cell membrane, thus
causing its damage. Glutathione is the main low molecular weight
antioxidant whose concentration in the erythrocyte is high (about
2 mM). This tripeptide is synthesized in the presence of ATP
without ribosomes.
The erythrocyte maintains the normal function despite cyclic
temperature differences (28
o
C in the pulmonary tissue and close
to 40
o
C in the liver and working muscles). High osmolality in kid
-
ney medulla additionally exposes erythrocytes to osmotic stress.
Erythrocyte diameter is larger than capillary diameter, causing
friction and deformation during the passage [15].
In
the body, the erythrocyte cytoskeleton is most of the time
forced to undergo structural rearrangements. The work coun
-
teracting these processes requires energy (ATP and reduced
pyridine derivatives). In humans, ATP in erythrocytes is formed
via the fundamental metabolic pathway, i.e. glycolysis (Fig. 3). In
the absence of mitochondria in erythrocytes glycolysis produces
lactate, which is removed from the cells.
The passage through metabolically active tissues, i.e. the
environment with high acid content (for instance skeletal mus-
cles), alters the rate of passage of
the intermediates through
the metabolic pathways in erythrocytes. Regulation of glycoly
-
sis in erythrocytes is especially sensitive to changes in acidity.
Reduced pH decreases the activity of phosphofructo-kinase-1
and other important allosteric enzymes: pyruvate kinase and
hexokinase. Hydrogen ions inhibit the reaction catalyzed by
bisphosphoglyceratemutase and stimulate phosphatase activity of
this bifunctional enzyme. Therefore, severe acidosis reduces the
concentration of 2,3-BPG and ATP in erythrocytes and increases
the afinity of hemoglobin for oxygen [11,16]. For this reason, red
cell glycolysis is very H
+
sensitive, being
stimulated by a rise in
pH. The available evidence suggests that the pH is the primary
controlling factor of erythrocyte metabolism.
