Adenosine triphosphate (ATP) is The fundamental unit of intracellular energy transfer. It is produced in mitochondria in humans. ATP is essential to maintaining the activity and operation of all cells. The mitochondria create most of the energy they use to generate ATP by creating a proton gradient across the inner mitochondrial membranes. This energy generation is done largely via the process known as the electron transport chain. This process is analogous to generating energy to pump water to the high side of a hydroelectric dam, except it’s protons, not water, that are pumped. This flow of protons back through the metaphorical dam powers the enzyme known as ATP synthase that in turn changes adenosine diphosphate (ADP) into ATP by adding a phosphate group.
The electron transport chain is a system inside of the mitochondria that provides most of the energy that creates the proton gradient that powers the ADP to ATP reaction via ATP synthase. There are other anaerobic systems for producing ATP in the body, including glycolysis, but they are far less efficient. The electron transport chain is active in producing ATP during aerobic exercise. At more strenuous levels of exertion, the less efficient glycolysis system generates ATP from pyruvate directly, but this generates lactic acid buildup which leads to fatigue. This aerobic to anaerobic switch under stress also occurs in the brain. As we all know, exercise can increase athletic endurance. This athletic endurance is tied to mitochondrial capacity and efficiency. There is some evidence that exercise increases mitochondrial capacity in the brain the same way it increases it in the body.
Some nootropics interact directly with the mitochondrial membranes. For example, in a recent study, piracetam protected mitochondria from the bacterial toxin known as lipopolysaccharide by shoring up mitochondrial membranes. It also improved mitochondrial integrity in healthy cells. In cell models piracetam has been shown to ameliorate degenerative impairment in the mitochondria caused by alzheimers like conditions.
Another interesting phenomenon at the mitochondrial membranes are uncoupling proteins. These proteins induce thermogenesis in mitochondria by letting electrons leak back through the membrane without generating ATP. It’s similar to opening up a flood gate to let water spill through the dam without going through the generators. This is another way of releasing stored energy besides aerobic energy generation. This process happens in mammals during hibernation. This process can be upregulated in brown adipose tissue found in the body by inhibiting PDE3 and PDE4. This uncoupling mechanism can induce thermogenic weight loss.
There are four different complexes in the electron transport chain that oxidize substrates to generate the energy to transfer protons out of the mitochondrial membrane. Each step of oxidation creates an incremental amount of energy for ATP production. The last step of the chain involves a chemical reaction with oxygen. Sometimes reactants skip a few steps and react directly with oxygen creating damaging free radicals. The three different complexes are NADH to NAD+ (Complex I), Succinate to Fumarate (Complex II) and CoQH2 to CoQ (Complex III) and O2 -> H20 (Complex IV). These complexes are amenable to optimization in various ways.
Our first metaphorical pumping station, Complex I, turns NADH to NAD+. It pumps protons by transferring electrons to coenzyme Q10 turning it into ubiquinol which, through a series of reactions, pump protons out of the membrane and to the high side of the metaphorical dam. Coenzyme Q10 and ubiquinol are both sold as supplements. Improvements in exercise performance for users of supplemental coenzyme Q10 are not significant nor has it shown much benefit in parkinson’s disease. The reduced form of coenzyme Q10, ubiquinol, has some interesting data. It enhanced athletic performance in healthy athletes and has shown some beneficial effects in studies in managing diabetes.
A synthetic analog of coenzyme Q10 known as idebenone has some interesting effects at complex 1. Idebenone’s mechanism of action may be in its ability to help utilize NADH to pump protons when complex 1 is not functioning properly, possibly via complex III. In studies it increased nerve growth factor production in an animal model of brain damage. In another study it slowed down the development of dementia symptoms in Alzheimer’s patients.
Complex ||, which converts succinate to fumarate can be protected from dysfunction by a combination of glutathione and vitamin C. In general studies have shown that vitamin C helps complexes I-IV of the electron transport chain function properly.
Complex III, uses cytochrome c to contribute to the mitochondrial power generation by converting ubiquinol back to coenzyme q10. There is some evidence that luteolin protects this process from antimycin-a which inhibits cytochrome c.
Complex IV, uses cytochrome c oxidase to turn oxygen to water for the last step of the electron transport chain. Interestingly, some evidence suggests that laser light therapy can increase its activity. Some studies were also done on methylene blue that provided some evidence for positive effects on cytochrome C oxidase in alzheimer’s patients.
These various complexes are like pistons in a gas powered pump. With each turn of the crank each cylinder fires and pushes the proton “water” up to the top of the dam. The mitochondria are at the core of many dysfunctions and problems in human health, including aging. Thus, targeting optimization and protection of these cell components is a fruitful area of investigation for those who want to enhance and improve their mental and physical performance.
Additional posts by Abelard Lindsay (@ciltep):
- The Nootropic Why
- Acetyl-L-Carnitine Exploring Its Cognitive and LTP Related Effects
- Magnesium L-Threonate Can Improve Brain Function and LTP
- CILTEP and Racetams: Evidence for a theory of complementary mechanisms of action
- Some Health Benefits of Resveratrol Could Theoretically Apply to CILTEP
- Assembling the Acetylcholine Puzzle Part 1
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