4.14 BCHM - Metabolic Changes of Aging Brain Flashcards
What happens to the energy the brain uses as we age (more or less)? What is this energy used for?
Use less energy as we age.
Brain uses energy to maintain ionic gradients (remember) and therefore as our brain shrinks we need less energy to maintain these gradients because there are less.
What happens to brains as we age? What about diseased brains?
Brain shrinks at a rate of ~0.2% per year.
Diseased brains shrink faster.
ROS, age, inflammation, vascularization, energetic, nutritional, diseases, telomeric clocks - these are all hypothesis about human aging. Is only one of these most likely the right answer? What is a prevalent theme among these hypotheses? why is the brain particularly vulnerable to the effects of aging?
Aging is most likely a multifactorial event: various combinations of the above mentioned are at play here.
Metabolism plays a central role among the hypotheses of aging.
The brain is extremely metabolically active, therefore it will be the first to show signs or be affected by metabolic problems.
The reactive oxygen species hypothesis of aging states that: age releated degenerative processes are a consequence of damage induced by ROS.
Name three facts that support this hypothesis.
Amount of free radicals in brain increases with age.
Amount of free radicals in brain correlates with various neurodegenerative diseases.
67yo produce 3X more ROS than 23yo.
ROS deficiency is harmful and ROS excess is harmful. Explain how this is possible (what is their role in the beneficial sense/ harmful sense)? What is the ROS relationship with oxidative stress?
ROS (aka: free radicals) are essential signalling molecules in our body, they can signal our body to come remove excess ROS.
Free radicals are chemically reactive and damage DNA, proteins, lipids.
Oxidative stress occurs when free radical production exceeds the antioxidant defense mechanisms. This results in oxidative damage of various cellular components: proteins, lipids, + nucleic acids.
Most ROS are formed by the electron transport chain. How would production of ROS vary between the CNS and other tissues in the body regarding the production of ROS?
CNS requires 10X more energy than most tissues therefore it prodcues 10X more ROS than most tissues. And unlike liver (for example) has less of a capacity to eliminate these free radicals.
Oxygen isn’t all bad though.. What is the main role/ necessity of oxygen in our bodies?
02 = final electron acceptor.
02 is very electronegative and in oxidative phosphorylation it bumps into electropositive cofactors bearing electrons and an oxidation-reduction reaction occurs.
What is the body’s primary source of ROS? What is the primary free radical being formed here?
Mitochondria is the body’s primary source of ROS.
Superoxide Anion: primary free radical formed in mitochondrial inner membrane. Constantly being formed.
Describe the process of superoxide anion formation? (how does it occur, why does it occur, how Americans harness this).
Superoxide anion is primarily made at complex 1 + 3 in oxidative phosphorylation.
02 is able to bump into electron carrying cofactors which freely give up their electrons to O2 making it superoxide anion.
If you consume more energy then you fart out, then you have a buildup of product (ATP), this buildup causes less ATP being made and more substrates (electron carrying cofactors) laying around. With more laying around in the membrane there is more potential for O2 to bump into them and do the process mentioned above.
Ubiquinone, semiquinone, and ubiquinol are all present in oxidative phosphorylation floating around in the mitochondrial membrane. Which is of these is most likely to donate electrons to O2, why? Which is least likely?
Ubiquinol will donate.
Ubiquinol is a REDUCED state and is carrying electrons that it will gladly hand over to O2.
Ubiquonone is a heavily oxidated state and is least likely to dontate electrons.
Semiquinone is in the middle.
Which of the following are considered free radicals? What does a compound have to have in order to be considered a free radical? Which of these is the primary free radical?
Free radicals are compounds that have a single unpaired electron.
By that definition superoxide anion, hydroxyl radical, and hydrogen peroxide (not sure why, but he said so) would be considered free radicals.
Primary damaging free radical is superoxide anion.
Semiubiquinone is the free radical form of ubiquinone, this molecule helps in the production of superoxide anion. Semiubiquinone is present at what complexes in the oxidative phosphorylation cycle? Which does not contribute a significant amount, how?
Present at complex 1, 2, 3. But mostly 1 + 3.
Complex 4 does not contribute a significant amount. Complex 4 binds O2 tightly and reduces O2 through free radical intermediates, but releases no significant amount of free radicals.
When there is a stall in oxidative phosphorylation but the citric acid cycle is still working away, what product is in excess here (via the ACA)? How does this result in excess ROS?
ACA makes NADH to spin oxidative phosphorylation, even though oxidative phosphorylation is stalled the ACA is still pumping away making NADH.
This NADH is donating electrons all day but the electrons are not going to the right place and are stuck in the mitochondrial membrane where they are subjected to being snatched up by O2. => superoxide anion (ROS).
Mitochondria is the primary source of production of ROS in the body, however it is also the primary source of ROS elimination in the body. What enzymes + cofactors are used to eliminate ROS? Draw that shit out!
Superoxide dismutase: converts superoxide anion -> hydrogen peroxide (H2O2).
Glutathione peroxidase: reduces H2O2 -> H20.
Glutathione reductase: reduces glutathione to restore its antioxidant capability.
Superoxide dismutase oxidizes and reduces superoxide anion. Which product resulted from oxidation, which from reduction? Think in your head about the products and hash it out before flipping.
H2O2 gets reduced. O2 is oxidized.
Glutathione peroxidase and glutathione reductase are at work in this process. Name which enzyme results in a reduced molecule and which an oxidized molecule? Then look at image and disect it.
Glutathione peroxidase => oxidizes.
Glutathione reductase => reduces.
Why does an increase in ROS concentration signal an increase in production of uncoupling protein in mitochondria?
The uncoupled protein, when signalled, comes in and forms a pore in the mitochondrial membrane.
This results in H+ falling into the cytosol of the mitochondria and binding with the excess electrons so that O2 won’t and therefore results in less ROS.
