Question

Leigh syndrome is a mitochondrial disorder that can be caused by a number of mutations. One of the more common mutations is a defect in the SURF1 protein which is responsible for correct insertion of cytochrome a3 in complex IV. The syndrome is usually triggered in infants by stress and leads to episodic developmental regression during times of stress. Other common symptoms can include excess lactate in body fluids and cardiomyopathy.

a) What are the biochemical results to be expected in a person with improperly functioning complex IV?

b) Do the physical symptoms of Leigh syndrome described above make sense in light of the biochemical effects?

Answer 1

Ans. #a. Complex IV transfers the high energy electrons (released during oxidation of NADH and FADH₂) to O₂ by reducing molecular oxygen to H₂O.

Presence of a mal-functional copy of complex IV may exhibit the inability to transfer the electrons generated during ETC to O₂, thus causing it to “freeze” in reduced state. Since the electron flow through the ETC complexes is sequential, freezing of complex IV also causes successive arrest of complex III, II and I in their reduced states. Ultimately, the whole ETC electron flow freezes.

The arrest of complex IV (in in turn, the other complexes) may exert following biochemical effects-

I. Inhibition of electron flow through ETC also inhibits establishment of proton gradient across inner mitochondrial membrane. Since proton gradient is the key to ATP production, a non-existing or inefficient proton gradient leads to low or NO ATP production during cellular respiration.

II. Shutting down of ETC also shuts down oxidative phosphorylation. So, glycolysis may be the only available metabolic pathways of cellular energy.

III. The electrons, if not transferred to O₂, will ultimately dissipate to the surrounding. The association of high energy electrons with molecules and biomolecules in the surrounding may lead to generation of free radicals. Free radicals may further lead to disintegration of lipid bilayers as well as biomolecules in the cell.

IV. The inhaled O₂ molecules, if not reduced into H₂O at complex IV, may also oxidize the biomolecules and may trigger of the cascade of abnormal reactions.

#b. Yes. Shutting down of ETC due to “freezing of complex IV in reduced state” leaves glycolysis as the next available source of ATP. For glycolysis to continue ceaselessly, its end product pyruvate must enter fermentation pathways to oxidize NADH back into NAD⁺. Fermentation of pyruvate in in muscles lead to formation of lactic acid (lactate).      

# Frozen complex IV leading to inefficient production of ATP during cellular respiration. Since cardiomyocytes are in ceaseless activity for heart to keep functioning, depletion of ATP supply to these cells may lead to cardiomyopathy.