Metabolic Energy Pathways

Question 1

What does food provide us with and what does it create?

Answer 1

• The components of foods provides us with amino acids, fats, and sugars. T
• hese get used by metabolic processes in the cytoplasm and mitochondria to create neurotransmitters, ATP, lipids, nucleotides, and essentially every biological process

Question 2

What uses glucose and fructose?

Answer 2

• Neurons use the glucose for generating ATP, whereas liver cells will use both glucose and fructose (for separate processes)
• Some evidence astrocytes can use fructose too

Question 3

How do we store food for later?

Answer 3

• Your body uses fatty acids for long-term storage in adipose (fat cells), and this lasts about 1 month without replenishment
• When you wake up in the morning, you are likely using your fatty acids to make ATP (ketosis)
• Your body uses sugar for short-term storage (called glycogen), and this would last you about a day

Question 4

What is one of the most energy consuming processes of your brain?

Answer 4

Maintaining the ionic gradient (i.e. the Na/K pump)

Question 5

What in your neurons is responsible for turning the oxygen and glucose into ATP?

Answer 5

• Glucose utilization (glycolytic metabolism

- Oxygen utilization (tricarboxylic acid cycle, TCA)

Question 6

Glucose utilization (glycolytic metabolism:

Answer 6

Glucose is metabolized via the glycolytic pathway, generating 2 pyruvate and 2 ATP; no oxygen is utilized in this pathway. This occurs in the neuronal cytoplasm.

Question 7

Oxygen utilization (tricarboxylic acid cycle, TCA) :

Answer 7

pyruvate (from the glycolytic cycle) and oxygen utilized to generate ATP. This occurs in the mitochondria.

Question 8

What is unique about the mitochondria?

Answer 8

• they are present throughout neurons due to need
• Mitochondria have a complex inner architecture, with an inner and outer membrane as well as their own mitochondrial DNA that is located in a nucleoid structure

Question 9

How does oxygen get into the brain?

Answer 9

Oxygen can freely diffuse through blood brain barrier and the cell membrane

Question 10

How does glucose get into the brain?

Answer 10

• Glucose is transported past the blood brain barrier to cells via transporters (GLUT)
• Glucose flows down its concentration gradient out of arterial flow, meaning brain glucose levels change with plasma glucose levels
• Glucose is transported to both astrocytes and neurons, with astrocytes playing a major role in metabolizing the glucose during brain activation.

Question 11

What do astrocytes do?

Answer 11

1) Astrocytes extend their processes around the capillaries and at every synapse in the brain.
A. Astrocyte capillary contacts can help maintain blood brain barrier integrity, have access to oxygen/glucose
B. Astrocyte synaptic contacts help with regulating signaling, and the astrocytes will express neurotransmitter receptors, transportes, and ion channels.
C. A single astrocytes is thought to contact up to 2 million synapses (top image, Belanger 2011)
A2) strocytes have just as many mitochondria as neurons
A. Astrocytes breakdown glucose preferentially into lactate to feed TCA cycle, whereas neurons use pyruvate

Question 12

What, where, and why of glycolysis

Answer 12

A. Glycolysis is an anaerobic process, meaning oxygen is not required
B. Glycolysis occurs in the cytoplasm of cells
C. Purpose of glycolysis is to generate ATP and Pyruvate (in neurons) from glucose, which will be used in the TCA cycle
1)Astrocytes will use glycolysis to make lactate. This lactate can then be shuttled to neurons for use in the TCA cycle during times of need or stress.

Question 13

What does glycolysis require and produce?

Answer 13

• Every glucose molecule requires 2 ATP to go through glycolysis, and in turn produces 4 ATP. This mean glycolysis produces 2 net ATP

Question 14

Glycolysis Step 1

Answer 14

• Step 1 (irreversible): glucose is catalyzed by the enzyme hexokinase (HK) to Glc6P. Significant because glucose is now trapped in the cell.

Question 15

After Step 1 how can Clc6P be used?

Answer 15

• Go to glycogen reserve
• Go to PP shunt pathway (nucleic acid synthesis)
• Continue with glycolysis

Question 16

Glc6P to glycogen

Answer 16

1) Glc1P prodices glycogen, which is the stored form of glucose your brain has.
2) The glycogen is the small reserve capacity your brain has to deal with abrupt increases in energy demand such as with excitatory transmission, ischemia or seizures
3) The process of utilizing glycogen is termed glycogenolysis.
A. Benefits over using glucose: reserve capacity during times of stress and does not require initial ATP like with glucose
4) Other cells in the body can create their own glucose in times of need, termed gluconeogenesis

Question 17

Glc6P to the PPSP

Answer 17

1) Generation of NADPH (used in glycolysis)
2) Producing nucleic acid precursors
3) In neurons, the PPSP is fueled by glucose whereas astrocytes use glucose and glycogen

Question 18

Glc6P to Fru6P (commitment)

Answer 18

• The enzyme PFK (phosphofructokinase) converts Fru6P to a byproduct.
  1) This step commits the Glu6P to the glycolytic pathway (as opposed to the other branch pathways)
  2) Up until this point, using glucose has used to ATPs, stored glucose as glycogen, and produced nucleotide precursors
  3) The remaining steps of glycolysis now must generate 4 ATP and pyruvate in order to feed into the TCA cycle

Question 19

How do the remaining steps from Fru6P to pyruvate generation produce the ATP needed? Steps 3-10

Answer 19

1) Redox signaling helps with this process
2) Electrons are removed from NAD+ to fuel the energy needed to turn ADP into ATP
3) The “used” NAD+, called NADH, now has to be regenerated for the next round of ATP generation. This cycle is called the malate-aspartate shuttle (MAS)
4) Think of NAD+/NADH as energy carriers, just like ATP