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CASE FILES: BIOCHEMISTRY
hyperthermia. Increased Ca2+ release triggers the binding of adenosine
triphosphate (ATP)-charged myosin to actin to initiate muscle contraction.
This muscle contraction may be repeated to the point of muscle rigidity with
attendant muscle damage and release of myoglobin. The sustained muscle
contraction uses increased amounts of ATP increasing demands on glycolysis,
tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. Ca2+ release
serves to activate, at least partially, phosphorylase kinase, which speeds the
mobilization of glycogen stores for ATP generation. Sympathetic outflow trig-
gered by these changes leads to increased activation of glycogen breakdown
and lipolysis. Fatty acids serve as a signal to increase the levels of uncoupling
proteins in various tissues. The uncoupling proteins form channels in mito-
chondria allowing proton reentry into the mitochondrial matrix. Because
the phosphorylation of adenosine diphosphate (ADP) to ATP depends on the
proton gradient through the ATP synthase, these channels collapse the proton
gradient allowing electron transport to occur without the phosphoryla-
tion of ADP (Figure 18-2). Since ATP is being consumed at an elevated rate
and mitochondrial production of ATP is compromised, glycolysis increases to
compensate for the shortfall in ATP production. Pyruvate and lactate, the
end products of glycolysis, increase in concentration, giving rise to the
metabolic acidosis observed.
The uncoupling proteins (UCP 1 to 5) are a physiologic mechanism for
maintaining body temperature through selective uncoupling of electron
transport from ATP synthesis. The free energy release normally captured in
the formation of the high-energy phosphate bond when phosphorylating ADP
to ATP is lost as heat and changes body temperature. Physiologically, sympa-
thetic outflow and catecholamine hormone release prompt new synthesis of
the uncoupling proteins in response to the hypothalamus sensing lowered body
temperature. In the case of malignant hyperthermia, this mechanism is trig-
gered by anesthetic challenge to the calcium release channel and the subse-
quent metabolic and signaling changes assembled above unfold.
ADP
ATP
inside
Carrier
Carrier
Carrier
electron
rnilo
C o m p le x
C o m p le x
C o m p le x
membrane
outside
Figure 18-2. Electron transport system showing development of proton gradient
outside the mitochondrial membrane by the passage of electrons down the chain.
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