Case study Malignant hyperthermia (Electron transport chain and oxidative phosphorylation)

Case details

A 23-year-old college foot ball player sustains a compound fracture on the field. He is taken to surgery, during which the anesthesiologist notes a significantly increased body temperature (102 0 F). The operation is terminated without completion, as malignant hyperthermia is suspected. Which of the following components of ETC is likely to be responsible for this phenomenon?

A. Complex I

B. Complex II

C. Complex III

D. Complex IV

E.  ATP synthase complex

Answer- The right answer is- E- ATP Synthase complex. Patients with malignant hyperthermia experience uncoupling of oxidative phosphorylation .

OXIDATIVE PHOSPHORYLATION

Chemiosmosis- As the electrons are transferred, some electron energy is lost with each transfer. This energy is used to pump protons (H+) across the membrane from the matrix to the inner membrane space. A proton gradient is established (Figure).The higher negative charge in the matrix attracts the protons (H+) back from the intermembrane space to the matrix.The accumulation of protons in the intermembrane space drives protons into the matrix via diffusion. Most protons move back to the matrix through ATP synthase. ATP synthase uses the energy of the proton gradient to synthesize ATP from ADP + Pi.

Electro chemical gradient

Figure- Showing electrochemical gradient across the inner mitochondrial membrane. The chemiosmotic theory, proposed by Peter Mitchell in 1961, postulates that the two processes are coupled by a proton gradient across the inner mitochondrial membrane so that the proton motive force caused by the electrochemical potential difference (negative on the matrix side) drives the mechanism of ATP synthesis.

Uncouplers are amphipathic and increase the permeability of the lipoid inner mitochondrial membrane to protons, thus reducing the electrochemical potential and short-circuiting the ATP synthase .In this way, oxidation can proceed without phosphorylation, the energy thus released is not captured to form ATP rather it is released in the form of heat, causing hyperthermia. There are a number of physiological and pathological uncouplers.

2,4-dinitrophenol, 2, 4- dinitrocresol , CCCP, TCCP, Valinomycin , high dose of Aspirin  are some of the uncouplers of oxidative phosphorylation. The antibiotic oligomycin completely blocks oxidation and phosphorylation by blocking the flow of protons through ATP synthase

Long chain fatty acids, thyroxin, brown Adipose tissue (thermogenin or the uncoupling protein is a physiological uncoupler found in brown adipose tissue that functions to generate body heat, particularly for the newborn and during hibernation in animals ) and Calcium ions are some of the physiological uncouplers of oxidative phosphorylation. Excess calcium released in malignant hyperthermia is responsible for uncoupling of oxidative phosphorylation.

There are  a number of site specific inhibitors of Electron transport chain that act as poisons.

Complex I is inhibited by Rotenone and Barbiturates such as Amobarbital that  inhibit electron transport by blocking the transfer from Fe-S to Q. At sufficient dosage, they are fatal in vivo.

Malonate is a competitive inhibitor of Complex II.

Antimycin A and dimercaprol inhibit the respiratory chain at Complex III.

The classic poisons H2S, carbon monoxide, and cyanide inhibit Complex IV and can therefore totally arrest respiration.

For further reading follow the links-

http://www.namrata.co/category/biological-oxidation/theory-notes-biological-oxidation/

http://www.namrata.co/electron-transport-chain-strictly-aerobic-a-brief-review/

http://www.namrata.co/category/biological-oxidation/power-point-presentations-biological-oxidation/

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