Key Regulatory Steps in TCA Cycle
During exercise, stimulation of the TCA cycle results principally from . . .
Decrease in the NADH/NAD+ ratio
Like pyruvate dehydrogenase, a major regulator of the flux through the TCA cycle is the NADH/NAD+ ratio. If this ratio is high, it means that little NAD+ is available to act as a cofactor in the oxidative steps of the cycle. This will tend to slow down the cycle.
Two mitochondrial enzymes involved in generation of NADH that bear remarkable structural homology are. . .
pyruvate dehydrogenase and α-ketoglutarate dehydrogenase
Oxaloacetate may. . .
. . .participate in the TCA cycle, or exit the mitochondrion to be decarbocylated and used as fodder for gluconeogenesis.
If energy levels are low, it will enter the TCA cycle to meet the energy demand via oxidative phosphorylation.
If energy levels are sufficient in the fasting state (which, remember, is mostly powered by fat-derived acetyl-CoA), it will exit the mitochondrion to take place in gluconeogenesis.
Fates of pyruvate
Regulation of pyruvate dehydrogenase
The conversion of pyruvate to acetyl-coA results in production of ___, but conversion of amino acids to acetyl-coA does not.
The conversion of pyruvate to acetyl-coA results in production of carbon dioxide, but conversion of amino acids to acetyl-coA does not.
Most ETC-derived ROS is generated in. . .
. . .complexes I and III.
Other metabolic intersections with the TCA cycle
Regulation of PDH in the fasted state
Overview of TCA cycle
Overview of Mitochondrial Metabolism
TCA Cycle from 1000 ft
Amino Acid Catabolism via the TCA cycle
Destructive ROS cycle
In the fasted state, pyruvate is primarily. . .
. . .conserved for gluconeogenesis. The fasted state relies on fat-derived acetyl-coA to power the citric acid cycle.
ETC Complex I
A higher proton gradient, while speeding up ATP synthase activity, . . .
slows the rate of the electron transport chain, as complex I, III, and IV must now compete with with the proton gradient in order to pump their protons across.
The most reactive form of ROS
Regulation of PDH in the fed state
Structure of pyruvate dehydrogenase
Prosthetic groups of pyruvate dehydrogenase
More detailed TCA cycle
Mitochondrial ROS generation is most likely to happen in coditions of. . .
NADH production higher than sufficient to meet the ATP needs of the cell. This is because the proton gradient will be excessive, and lead to ETC slowing. When the ETC is slowed down, it is more prone to ROS generation at complex I and III.
This can be protected against by halting NADH generation when ATP needs are met.
The Electron Transport Chain
___% of ROS in the human body comes from the electron transport chain.
85% of ROS in the human body comes from the electron transport chain.
In metabolism, cells always prioritize ___.
In metabolism, cells always prioritize sufficient intracellular ATP.
Citrate may be utilized for ____ in addition to its role in the TCA cycle.
Citrate may be utilized for fatty acid synthesis in addition to its role in the TCA cycle.
Final Steps of TCA cycle
If Acetyl-CoA levels are high, and ATP/NADH levels are high, ___.
If Acetyl-CoA levels are high, but ATP/NADH levels are low, ___.
If Acetyl-CoA levels are high, and ATP/NADH levels are high, pyruvate carboxylase and PEP carboxykinase will both activate, stimulating gluconeogensis.
If Acetyl-CoA levels are high, but ATP/NADH levels are low, pyruvate carboxylase, but not PEP carboxykinase, will activate, stimulating oxaloacetate generation and re-entry of oxaloacetate into the TCA cycle.
Pyruvate dehydrogenase is activated by ___.
Pyruvate dehydrogenase is activated by NAD+.
Converts two ADP to one ATP and one AMP.
When you are severely depleted of oxygen, ADP levels go down. This is because under severe energy depletion, two ADPs will be converted into ATP and AMP
In an uncoupled state, the ETC will move. . .
in part because they are pumping against less of a gradient → less work, less of a thermodynamic barrier
Currently under trials to mitigate damage during ischemia reperfusion injury.
Blocks the activity of succinate dehyrogenase.
The link between complexes I, II, and III
Ischemia reperfusion injury
ischemia → succiante buildup
reperfusion → e- overload, massive complex I ROS generation