Metabolic Energy Pathways II

Question 1

The main purpose of the Krebs cycle is

Answer 1

to take the pyruvate generated from glycolysis and turn that in to energy (i.e. ATP)

Question 2

How does TCA differ from glycolysis

Answer 2

TCA is aerobic in that it utilizes oxygen

Question 3

What is the start of the TCA cycle?

Answer 3

Pyruvate, the product of glycolysis, is converted to acetyl CoA in the mitochondria

Question 4

Where does the TCA cycle take place?

Answer 4

the mitochondria

Question 5

What process in the mitochondria produces ATP

Answer 5

the electron transport chain

Question 6

The net effect of TCA, glycolysis, and MAS cycle

Answer 6

1 glucose produces 32 ATP and uses 6 O2

Question 7

In addition to ATP the TCA cycle also produces

Answer 7

neurotransmitters like glutamate and acetylcholine

Question 8

Neuronal replacements for glucose

Answer 8

1. ketones - through fatty acid breakdowns
2. lactate - through astrocyte metabolism
3. glutamate - continually by astrocytes to regulate glutamate signaling and produce ATP
4. glycogen - to produce limited ATP in times of stress

Question 9

4 causes of metabolic disorders

Answer 9

1. fuel delivery disruptions (ischemia, hypoxia)
2. inadequate nutrition/vitamin deficiency
3. mitochondrial defects
4. glycogen metabolism

Question 10

Diabetes definition and types

Answer 10

• metabolic disorder that results from not enough insulin
• Type I: loss of insulin producing cells in pancreas
• Type II: reduced insulin sensitivity of cells

Question 11

What does insulin normally do?

Answer 11

Insulin regulates glucose uptake– when you eat, insulin is released and it promotes glucose utilization by tissue and conversion to glycogen (for later use)

Question 12

WHat happens without insulin?

Answer 12

Without insulin or with cells that are resistant to insulin, you end up with elevated blood glucose levels and not enough glucose getting to your cells
- effects protein synthesis, metabolism, possibly cognition

Question 13

DIabetes: Hypoglycemia

Answer 13

• low blood glucose levels
• result from taking too much insulin or not eating enough food
• this lowers the available glucose in the blooD

Question 14

BBB and blood diffusion

Answer 14

Remember that glucose gets through the BBB via diffusion, so if the blood glucose levels fall, the concentration gradient is no longer present

Question 15

Glucose can no longer enter neurons if blood glucose dips too low, meaning

Answer 15

• hexokinase enzyme is no longer working at full capacity
• pyruvate production falls as a result and the TCA cycle does not have the same supply of pyruvate as it once had
• overall ATP production is significantly lowered

Question 16

CNS symptoms of hypoglycemia

Answer 16

• abnormal thinking, feeling numb, fatigue, blurred vision, headache, coma, seizures

Question 17

Hypoglycemia: 3 ways reduction in glucose could affect the brain

Answer 17

1. PPSP pathway - no nucleic acid synthesis
2. No ATP = no ionic gradients necessary for action potentials
3. active transporters, vesicular trafficking, protein synthesis all affected

Question 18

Treatment for hypoglycemia

Answer 18

• eating something that will cause a sharp increase in blood glucose levels

Question 19

Hypoxia definition and causes

Answer 19

• an inadequate level of inspired oxygen in the air
• result from increased altitude, the decrease in atm pressure reduces driving pressure for gas exchange in the lungs, or the lungs struggle to pull in oxygen and pass it to the blood decreasing blood concentration of oxygen

Question 20

Why is your brain MUCH more sensitive to a decrease in oxygen than glucose?

Answer 20

1. glycogen exists to make up for low glucose

2. glycolysis which does not require oxygen, makes very little ATP compared to the TCA cycle

Question 21

Acute and Chronic hypoxia

Answer 21

Acute: neurotransmitter synthesis decrease
Chronic: HIF-1 senses oxygen levels and increases glucose transporters and glycolytic enzymes - effort to increase anaerobic ATP production

Question 22

High altitude mountain climbing also produces hypoxia

Answer 22

• climbers of the highest mountains spend time acclimating at higher altitudes to prepare, though altitude sickness due to hypoxia is very common
• Altitude sickness is deadly: disorientation, hallucinations, impaired judgements, fatigue, and vision changes can all occur

Question 23

In a study by Nicolas Fayed, MRI scans of 35 high altitude climbers found brain damage in almost all of the climbers, even ones who had done smaller peaks
Why do mountain climbers display this?

Answer 23

1. Decrease in oxygen makes our bodies produce more red blood cells to compensate for less mitochondrial ATP/cycle
2. Extra red blood cells thickens the blood and makes it harder for the heart to pump it (increases blood pressure)
3. Capillaries can then create edema and are more likely to clot and produce strokes

Question 24

In the study, people who had climbed mountains 1/3rd the size of Everest almost all came back with

Answer 24

cortical lesions, ventricular space swelling, memory problems, slowed mental function etc.

Question 25

Then how do communities that live permanently at high altitudes, like Sherpas, survive?

Answer 25

- Sherpas have better muscle energy metabolism, driven by certain genes involved in the metabolic pathway - Anerobic lactate production, such as what astrocytes use during times of stress, was 48% higher in sherpas indicating they are better able to deal with muscle metabolic stress

Question 26

How is hypoxia treated?

Answer 26

- Based on the cause, it would first involve removing individual from situation (high pressure, high altitude, etc.) - Simultaneously, you would also want to: a) Increase inspired oxygen concentration b) Medications for blood pressure, clotting, and vasodilation (depending on source of hypoxia) - Based on the Sherpa data, there is interest in instead targeting metabolic pathways involving oxygen versus oxygen itself

Question 27

Ischemia definition and causes and symptoms

Answer 27

- the blockage of blood flow, which eliminates supply of BOTH oxygen and glucose - Ischemia can result from a blood clot, vascular damage or a secondary effect of a heart attack - CNS symptoms of brain ischemia (i.e. stroke): inability to move on one side, problems understanding or speaking, loss of vision, headache

Question 28

What happens with ischemia?

Answer 28

- Oxygen depletion prevents metabolism of amino acids and TCA cycle (ATP decrease) - Glucose depletion results in glycogen usage from astrocytes. These astrocytes will turn the stored glycogen into lactate, and shuttle that to neurons - Ion pumps fails and glucose transporters actually reverse direction, pumping glucose out of neurons - This causes glucose to bind to other neurons, producing excitotoxicity

Question 29

Ischemia effects on energy, mitochondria

Answer 29

- Total energy failure occurs within 60s of ischemia and results in loss of consciousness - Mitochondria themselves can be affected due to excitotoxicity so you get even more energy depletion (no TCA cycle or electron transport chain) - Brief energy failure does not kill brain cells—cell death requires longer ischemic episodes - Treatment: tPA (dissolves blot clots), surgical removal of clot

Question 30

Mitochondrial Mutations

Answer 30

- Glycolysis and TCA cycle both require the mitochondria - Thus, mitochondrial mutations can have severe cognitive effects depending on the severity of the mutation. - Symptoms can vary widely from “exercise intolerance” to severe neurological issues and dysfunction

Question 31

How do mitochondrial mutations occur?

Answer 31

- Mitochondrial DNA is inherited solely from the female (contained in egg). - Mitochondrial disease can result from a mutation to any component of the TCA cycle/electron transport chain

Question 32

How can mitochondrial disease be treated?

Answer 32

1) Vitamins and supplements 2) Nutrition and general health 3) Exercise 4) Mitochondrial transfer