S1B4 - Electron Transport Chain Flashcards Preview

Molecular oxygen, O2, is the final electron acceptor.

ATP Synthase (Complex V): uses the electrochemical proton gradient created by the ETC to produce ATP from ADP and Pi.

Electron transport chain (oxidative phosphorylation): uses NADH and FADH2 electrons (from glycolysis, pyruvate dehydrogenase complex, and the citric acid cycle) to form a proton gradient. The proton gradient drives the production of ATP.

The ETC (electron transport chain) is composed of 5 multi-enzyme complexes, numbered I-V. It is embedded in the inner mitochondrial membrane.

C) Cytochrome c oxidase

CO binds to cytochrome c oxidase in the electron transport chain.

1 NADH yields Ž2.5 ATP and 1 FADH2 yields Ž1.5 ATP. The reason for the lower energy yield of FADH2 is that NADH electrons are transferred to complex I while FADH2 electrons are transferred to complex II. 

• Complex II is succinate dehydrogenase of the citric acid cycle.

Mobile electron carriers coenzyme Q and cytochrome c shuttle electrons between enzyme complexes of the ETC.

• coenzyme Q shuttles electrons from complexes I and II to complex III.
• cytochrome c shuttles electrons from complex III to complex IV.

The flow of electrons (provided by NADH and FADH2) through the ETC provides the energy to pump protons into the mitochondrial inter-membrane space. This creates an electrochemical proton gradient.

Administration of thiosulfate causes cyanide to react with enzyme rhodanese, forminga nontoxic thiocyanate.

• Point mutations on the genes encoding mittRNA result in two most common mitdiseases characterized by encephalomyopathy
• Lys mutation in tRNA causes myoclonic epilepsy and ragged red fibers (MERRF)
• Myoclonus and ataxia with seizures and myopathy are associated with this disease. Skeletal muscles contain abnormal mit with paracrystalline structures appearing as ragged red fiber with decreased cyt oxidases
• Mutation in tRNA for Leu causes the common mitochondrial encephlopathy, lactic acidosis and stroke-like activity (MELAS). Skeletal muscle contain ragged red fiber but retain cyt oxidase activity
• More than 85% mutation results in severe CNS symptoms, and 5%-30% mutated DNA patients show maternally inherited diabetes mellitus and deafness
• Both tRNA mutations impair mitprotein synthesis leading to decreased activities of complex I and cyt oxidase

• In 1993 cyt b mutation resulting in lower cyt bc1 complex activity was reported in a 25 year old man.
• Other mutations G290D, G339E, G34S, and G166E observed. D/E mutations occur on cyt b close to Qo and S mutation close to Qi site for ubiquinone  oxidation and reduction respectively
• All the mutations involve guanine to adenine transition in mitDNA indicating that the mutations have resulted from oxidative damage
• Replacement of G by larger charged molecule alter the structure of cyt b resulting in lowered catalytic activity of bc1 complex.
• Truncation and deletion of 4 to 24 base pairs from nonsense mutations often lead to severe exercise intolerance, lactic acidosis in resting state and occasional myoglobinuria.
• In contrast to majority of mtDNAmutations, cyt b mutations are not maternally inherited. Also, they are mainly in muscle tissue suggesting somatic mutations

• NADPH-dependent oxidase (NOX) in phagocytic and other cells produces large amounts of superoxide to kill microbes.
• Mutations in NOX results in inability to produce adequate amounts of superoxide to combat infections
• There are 7 different isoforms of NOX family in all tissues of the body. Theses isoforms are thought to contribute in maintaining the vascular tone , cell proliferation, angiogenesis, and apoptosis
• Despite the beneficial role of NOX in cell processes, excess ROS generated by NOX results in pathophysiological conditions including, endothelial cell dysfunction that contributes to atherosclerosis, hypertension, congestive heart failure, ischemic reperfusion injury, diabetic vascular problem.
   

• Early reperfusion with appropriate therapy after myocardial infarction results in reduction of the infarct size and better clinical outcome
• Restoring blood flow to the ischemic tissue, however, may damage heart termed as myocardial reperfusion injury
• Such a damage comes from damage to myocardium due to rapid restoration of electron transfer through mt ETC with concomitant generation of ROS
• ROS are also generated by xanthine oxidase of endothelial cells and by NADPH oxidase of neutrophils

Batten’s disease

Lysosomal storage disease where the subunit c of ATP synthase has been found as a predominant storage protein
 

Alzheimer’s disease

Progressive degenerative brain disease in which  a deficiency of ATP synthase has been observed in mitochondria.
 

Drug-resistant strains of Mycobacterium

R207910, blocks the synthesis of ATP by targeting subunit c of ATP synthase
 

Tumor angiogenesis

ATP synthase inhibitors shown to inhibit migration and proliferation of endothelial cells with little effect on intracellular ATP
 

Lupus erythematosus

Bz-423, kills pathogenic lymphocytes selectively by inducing apoptosis in lymphoid cells

Leigh syndrome, ataxia, and retinitis pigmentosa syndrome

Neurodegenerative disease causing neuromuscular disorder with a 50% survival rate. Severe impairment of ATP synthesis due to a mutation in subunit a of ATP synthase.
 

Antiobesity

Inhibition of nonmitochondrial ATP synthase inhibits the cytosolic lipid droplet accumulation, suggesting ATP synthase as a molecular target for antiobesity drugs.
 

Antiangiogenic therapeutic strategy 

Inhibitors with the nonmitochondrial ATP synthase of endothelial cells inhibit the migration and proliferation of endothelial cells with little effect on intracellular ATP synthase, suggesting for an antiangiogenic therapeutic strategy to block tumor angiogenesis.
 

Blood pressure

ATP synthase F6 subunit circulating in the blood has been recognized to be involved in the increase of blood pressure.
 

maternal