Mitochondrial Disorders Pt. 1

Question 1

Define “metabolism”

Answer 1

How the body (all organs, all cells) functions by generating energy through intricate chemical steps from daily nutrition/food consumption.

Question 2

Define “basal metabolic rate”

Answer 2

Minimum calories needed at rest for energy for overall cell/organ function. This includes functions such as:

• Ion transport
• Digestion
• Brain activity
• Gut movement
• Breathing
• Heart pumping

Percent of Basal Metabolic Rate: Muscle (20%), Liver (19%), Brain (17%), Digestion (10%), Heart (8%), Kidneys (7%), Fat (3%), rest is misc.

Question 3

Name some things that impact your overall metabolic rate

Answer 3

Resting metabolic rate: warmth regulation, digestion, other processes
Daily activity: physical, mental
Demographics: gender, age, physique

Question 4

What are the 4 components of food?

Answer 4

Fat, Carbs, Protein, Vitamins

Question 5

What is the function of a vitamin?

Answer 5

Cofactor for crucial metabolic pathways

Question 6

What is the normal pH that is essential for proper functions of all enzymes in the body?

Answer 6

7.4

Question 7

Name a change from the norm (homeostasis) that can be life threatening

Answer 7

Acidosis (particularly lactic acidosis)

Question 8

What is it called when protein breakdown happens during illness?

Answer 8

Catabolism

Question 9

What is the main energy source for your cells?

Answer 9

Glucose

Question 10

Blood glucose needs to be between ___ - ___ mg/dL for adequate function of organs (including the brain)

Answer 10

80-120 mg/dL

Question 11

___ is how extra glucose is stored and also what is converted back into glucose when needed

Answer 11

Glycogen

Question 12

Where are fatty acids absorbed?

Answer 12

Gut

Question 13

Where are fatty acids processed?

Answer 13

Liver

Question 14

where does energy metabolism occur?

Answer 14

Mitochondria

Question 15

What are stored for energy once glucose/glycogen stores are depleted?

Answer 15

Fatty Acids

Question 16

Fatty Acids are the main source of energy for what?

Answer 16

Muscle, including the heart

Question 17

Enzyme defects can be partial or complete. What determines the severity and onset of illness?

Answer 17

Residual or remaining enzyme activity

• Mild –> teenage/adult presentation
• Severe –> newborn

Question 18

What might you need to measure enzyme activity, since direct can be difficult?

Answer 18

Tissue Biopsy

Question 19

What does Mitochondrial Dysfunction result in?

Answer 19

Cell injury –> cell death –> organ failure

Question 20

What organs are most impacted by mitochondrial dysfunction?

Answer 20

Organs w/ high energy demand

• Muscle (cardiac and skeletal)
• Endocrine organs
• Kidneys
• Intestinal tract
• Retina
• CNS

Question 21

Define “mitochondrial disease”

Answer 21

Chronic disorders that occur when mitochondria in numerous cells fail to produce sufficient energy for adequate function w/ subsequent organ failure

Question 22

Mito diseases are the result of either ___ or ___ mutations in ___ or ___

Answer 22

inherited, spontaneous, mtDNA, nDNA

Note: these mutations lead to altered function of proteins or RNA inside the mitochondria

Question 23

Name 6 other major metabolic pathways that mitochondria are involved in

Answer 23

• Purine/pyrimidine biosynthesis
• Heme synthesis
• Urea cycle
• Cholesterol metabolism/hormone synthesis
• Neurotransmitter metabolism
• Free radical production and detoxification

Question 24

What are mitochondria prone to?

Answer 24

Environmental insults such as aging, drugs, etc.

Question 25

What is meant by "mitochondria are dynamic organelles"?

Answer 25

They divide, fuse, and migrate

Question 26

True or false: a single cell can contain both mutant/defective mitochondria and normal mitochondria

Answer 26

True Note: this is why symptoms can be so variable b/w individuals in the same family. Ratios can also change over time and as we age, we all get mitochondrial damage

Question 27

What 6 things occur in cells w/ defective mitochondria?

Answer 27

- No ATP - Backlog of unused fuel molecules and oxygen (free radicals toxic to cell) - Inadequate oxygen supply - Lactic acidosis damages muscle and nerve tissue - Reactive oxygen species - Vitamins/antioxidants target this issue to minimize tissue damage

Question 28

What is the ONLY way we can measure activity of the electron chain complexes (in the oxidative phosphorylation process/respiratory chain)?

Answer 28

Must use fresh or frozen muscle biopsy, fresh is optimal for evaluation Note: only a few labs still do this testing since it's mostly been replaces by genetic testing

Question 29

How many genes does it take to make a mitochondrion?

Answer 29

3000

Question 30

What is the only metabolic pathway under dual control of both the mtDNA and nDNA genomes?

Answer 30

Electron transport chain

Question 31

Regarding the genes that control the electron transport chain: nDNA has ___ genes and has ___ inheritance pattern vs. mtDNA has ___ genes and has ___ inheritance pattern

Answer 31

850 genes, AR vs. 13 genes, Mitochondrial inheritance through maternal circular DNA

Question 32

Describe mtDNA

Answer 32

- closed, circular - maternally inherited - thousands of copies per cell - copy number is very dynamic

Question 33

What are 3 concepts that impact the effect of a mitochondrial disease on a person?

Answer 33

- Heteroplasmy: presence of mixture of mutant and normal mtDNAs - Tissue distribution: which tissues have the mutant mtDNAs - Threshold effect: vulnerability of each tissue to impaired oxidative metabolism Note: at cell division, mitochondria are distributed unequally and do not necessarily reflect the ratio found in the progenitor cell