Regulation by covalent modification and allosteric effectors (ATP-ADP)
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The main target for regulating oxidative phosphorylation appears to be Complex IV. It is phosphorylated in response to hormone action (Chapter 12) by cyclic-3'5'-adenosine monophosphate (cAMP)-dependent protein kinase (PKA) and dephosphorylated by a Ca2+-stimulated protein phosphatase. Phosphorylation enables allosteric regulation by ATP (ATP/ADP ratio). A high ATP/ADP ratio inhibits, and a low ratio stimulates oxidative phosphorylation. It is thought that the complex is normally phosphorylated and inhibited by ATP, but with high Ca2+ levels, e.g. in muscle during exercise (Chapter 19), the enzyme is dephosphorylated, the control by ATP/ADP is abolished, and its activity greatly stimulated, increasing ATP production.
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CYANIDE AND CARBON MONOXIDE ARE MITOCHONDRIAL POISONS |
Both cyanide and carbon monoxide bind to hemoglobin and inhibit oxygen transport. They also inhibit electron transport and production of ATP. |
Comment. Cells respond to cyanide or carbon monoxide poisoning by switching to anaerobic metabolism, resulting in lactic acidosis and ultimate death, unless immediate measures are taken. Carbon monoxide poisoning is treated with oxygen. In both cyanide and carbon monoxide poisoning, methylene blue can be administered: it alleviates the inhibition of Complex IV by accepting electrons from Complex III (cytochrome c reductase), allowing both Complex I and Complex III to pump protons, so that ATP can continue to be synthesized. Cyanide can also be converted to the relatively harmless thiocyanate ion by the administration of thiosulfate. |
MITOCHONDRIAL ENCEPHALOMYOPATHY |
A 16-year-old boy presented with headache, seizures and visual loss. There was a long history of inability to exercise due to muscle weakness. There have been episodes of hemianopia and mild hemiparesis lasting several days. His maternal aunt had a similar illness. Accumulation of lactate during and after exercise suggested a defect in mitochondrial oxidative metabolism. Muscle mitochondria were isolated for study. Respiratory Complex I activity was reduced. A point mutation in mitochondrial DNA was identified. |
Comment. A diagnosis of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) was made. MELAS is one of a group of conditions caused by defects in oxidative phosphorylation and characterized by defects in the process whereby NADH drives electrons along the mitochondrial respiratory chain complex and generates ATP. |
Complex I is also reversibly phosphorylated/dephosphorylated. Phosphorylation is catalyzed by a cAMP-dependent protein kinase and dephosphorylation by a Ca2+-inhibited protein phosphatase. Phosphorylation increases activity, which is maintained at high Ca2+.
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Lastly, based on the observation that in type 2 diabetes, ATP production is decreased when the β-subunit of ATP-synthase is phosphorylated, it has also been proposed that this complex is also regulated by phosphorylation/dephosphorylation.
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