Mitochondrial theory of ageing

Question 1

What is the connection between ROS and Life span?

Answer 1

Indirectly proportional.

Question 2

How is ROS produced in the mitochndria?

Answer 2

• O2 radical generated by complexes
• Converted to H2O2 by superoxide dismutase
• H2O2 converted to OH radical.
• H2O2 detoxified to H2O

Question 3

What is the principle of the vicious cycle hypothesis?

Answer 3

MtDNA is a prime target for ROS due to location, so they become damaged and produce damaged proteins which may produce more ROS.

Question 4

What are the 2 types of somatic mtDNA mutations in ageing?

Answer 4

• Large-scale mtDNA deletions
• Point mutations

Question 5

What are Mitochondrial DNA deletions?

Answer 5

Large-scale mitochondrial DNA deletions are a main form of mtDNA rearrangement.

Question 6

Where do Mitochondrial DNA deletions take place?

Answer 6

Most are found in the major arc of the genome.

Question 7

What are Mitochondrial DNA point mutations?

Answer 7

Substitution of single base pair

Question 8

Where do Mitochondrial DNA point mutations take place?

Answer 8

Found to be randomly located throughout the genome

Question 9

What are Mitochondrial DNA point mutations caused by?

Answer 9

Combination of errors during mtDNA replication and base misincorporation.

Question 10

What is clonal expansion?

Answer 10

The mechanism by which one mutated mtDNA molecule becomes the dominant species in an individual cell

Question 11

What are the 3 hypothesis for clonal expansion?

Answer 11

• Survival of the smallest
• Survival of the slowest
• Random Genetic drift

Question 12

What is the principle of the survival of the smallest hypothesis?

Answer 12

Molecules which are smaller due to a deletion of the mtDNA out-compete wild type molecules due to faster replication.

Question 13

What is the principle of the survival of the slowest hypothesis?

Answer 13

Dysfunctional mitochondria will have low levels of oxidative damage and will not be targeted by Lysosomes.

Question 14

What is the issue with the survival of the slowest hypothesis?

Answer 14

Does not take into account the dynamic reticular
network which is the normal state, it assumes they are individual organelles.

Question 15

What is the principle of random gentic drift in post mitotic cells?

Answer 15

MtDNA turnover occurs randomly so you can get expansion or loss of damaged cells.

Question 16

What is TFAM?

Answer 16

Responsible for mitochondrial transcription.

Question 17

What happen when TFAM was knocked out in the pancreas beta cell of a mouse?

Answer 17

Had similar thing to age-related diabetes.

Question 18

What happen when TFAM was knocked out in the Dopaminergic neuron TFAM mutant of a mouse?

Answer 18

Show mtDNA depletion
Respiratory chain deficiency
Slow progressive movement disorder similar to Parkinson’s disease.

Question 19

What happens when the mutator mouse phenotypes were changed in the small intestine?

Answer 19

Increased cell proliferation
Decreased fat absorption
Altered stem cell cycling
Increased apoptosis

Question 20

What happens when the mutator mouse phenotypes were changed in the skeletal muscle?

Answer 20

Induced mitochondrial dysfunction
Apoptosis
Sarcopenia

Question 21

What happens when the mutator mouse phenotypes were changed in the blood?

Answer 21

Macrocytic anaemia

Question 22

What are the Limitations of the mutator mouse?

Answer 22

• Mutation frequency higher than in aged humans
• Mutations occur from 7 days post-conception in mice, not sure when in humans.
• Different mechanisms of mutation occurrence
• Different mtDNA mutational spectrum

Question 23

How do maternal transmissions of mtDNA mutations accelerate ageing?

Answer 23

*Maternally transmitted mtDNA mutations can induce mild ageing phenotypes in mice
* Increase clonal expansion of mtDNA mutations