Mitochondria and ageing 02/04

Question 1

Why do mitochondria become damaged/dysfunctional with age?

Answer 1

Mitochondrial DNA resides in the matrix in circular form. It lacks histones and has relatively few repair enzymes. It is also very close to the site of ROS production. Therefore it is vulnerable to damage. As DNA mutations accumulate, mitochondria lose their ability to divide, and eventually become too big to be autophagocytosed and so they accumulate within the cell.

Question 2

What are the consequences of MtDNA damage?

Answer 2

1. Cells accumulate mitochondria with mutations in their DNA 2. Mitochondria produce more ROS 3. Electron transport chain complex activity declines 4. ROS are transferred to neighbouring cells 5. Cells die by necrosis, leading to inflammation

Question 3

Why do mitochondria accumulate?

Answer 3

They increase in size, as they are no longer able to divide.
Normal degradation by autophagy cannot occur.

Question 4

What is lipofuscin?

Answer 4

It is a pigment which is the ‘wear and tear’ marker of damage

Question 5

What are the modes of cell death and what determines which occurs?

Answer 5

Apoptosis - programmed cell death. A controlled process where parts of cell are partitioned off and degraded.

Necrosis - cell swells and leaks pro-inflammatory agents (proteases, lysozymes), spreads process to neighbouring cells. inflammation occurs

Cells require energy to undergo apoptosis - ATP levels determine it.

Question 6

Mitochondrial and nuclear DNA damage markers correlate with age. What does this suggest in terms of DNA damage?

Answer 6

• mitochondrial ROS may spread to other parts of cell, especially once highly reactive species like superoxide and OH are degraded to less reactive species like h202. protein and lipid peroxidation could also cause spread
• if nuclear DNA is damaged, then this can also effect complex II (the only complex encoded in nucleus as opposed to mitochondrial)

Question 7

In which complexes have mutations been identified?

Answer 7

ALL

Therefore both nuclear and mitochondrial damage can affect mitochondrial function

Question 8

what are the sex differences implicated in mitochondrial dysfuncton?

Answer 8

Old females have higher mitochondrial damage in complex III, Subunit 2 of complex IV and for complex V than old males (monkeys)

Question 9

Three pieces of causal experimental evidence for correlation between reduced mitochondrial function/mutation and reduced lifespan

Answer 9

1. Mice KO for mitochondrial SOD show reduced lifespan
2. Polg exonuclease excises incorrect bases during mtDNA replication. Mice homozeygous KO for polg have increased mutations in brain and heart and reduced lifespan. However heterozygous mice have increased mutation frequency, but no decreased lifespan.