CLINICAL CASES
135
succinate thiokinase with the release of free CoA. The high energy released
in the hydrolysis of the thioester bond of succinyl-CoA drives the phosphory-
lation of GDP to produce GTP. Succinate is then converted to oxaloacetate
in a series of reactions reminiscent of the P-oxidation of fatty acids. A double
bond is introduced into succinate in an oxidation catalyzed by succinate dehy-
drogenase, the only membrane-bound enzyme in the TCA cycle. The
reducing equivalents are captured as FADH2. The resulting fumarate is then
hydrated to form malate by the enzyme fumarase. Oxaloacetate is then
regenerated by the oxidation of malate by malate dehydrogenase with the
production of another NADH + H+.
Although the TCA cycle does not directly involve the participation of
molecular oxygen as a substrate, the reduced cofactors NADH and FADH2
must be reoxidized by the mitochondrial ETS for continued operation of the
cycle. Thus, the rate of oxidation of acetyl-CoA by the TCA cycle is to a
large degree regulated by the availability of the oxidized cofactors NAD+
and FAD. When tissues do not receive enough O2 as a result of hypoperfusion,
the ETS cannot regenerate these cofactors at a sufficient rate and the reactions
that use them are inhibited because one of the required substrates is lacking
(acceptor control). Thus, acetyl-CoA builds up in the mitochondria, depleting
free CoA levels. Decreased levels of NAD+ and CoA also inhibit the conver-
sion of pyruvate to acetyl-CoA by pyruvate dehydrogenase.
When the ETS and oxidative phosphorylation are compromised by a lack
of O2, cytosolic levels of ATP drop while ADP and AMP levels increase.
The flow of glucose through the glycolytic pathway is increased because of
allosteric activation of phosphofructokinase and pyruvate kinase by the
drop in ATP and rise in AMP concentrations. This results in an increased pro-
duction of NADH and pyruvate by the glycolytic pathway. However, since
electron transport is inhibited by a lack of O2, regeneration of NAD+ by the
glycerol 3-phosphate or malate-aspartate shuttles, and the ETS is also
inhibited. To continue the production of ATP by the glycolytic pathway,
NAD+ must be regenerated to accept more reducing equivalents when
glyceraldehyde 3-phosphate is oxidized to 1,3-bisphosphoglycerate. Lactate
dehydrogenase is activated by increased levels of pyruvate and NADH and
converts pyruvate to lactate with the regeneration of NAD+ (Figure 14-2).
Lactate that cannot be reused by the cells that produce it is transported out
of the cell to the bloodstream.
Lactate has two metabolic fates, either complete combustion to CO2 and
H2O or conversion back to glucose through gluconeogenesis. Both processes
require an active ETS and oxidative phosphorylation. Reduced oxygenation of
cells thus decreases the utilization of lactate and increases its production with
a resulting lactic acidosis.
When tissues are hypoperfused, the resulting anaerobic conditions have
energetic consequences. First, all catabolic processes that require an active
ETS and oxidative phosphorylation (e.g., P-oxidation of fatty acids and
amino acid breakdown) are inhibited. Thus, certain energy stores cannot be
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