Mitochondrial Inheritance

Question 1

How many mitochondria are in a cell?

Answer 1

Hundreds

Question 2

How many copies of mitochondrial DNA are there per mitocondria?

Answer 2

10 copies mtDNA/mitochondria

Question 3

How many copies of mitochondrial DNA are there per cell?

Answer 3

100-1000 copies/cell

Question 4

How many copies of mitochondrial DNA are there in a mature oocyte?

Answer 4

100,000 copies mtDNA/cell

Question 5

OXPHOS (Oxidative Phosphorylation) is central to these 3 major funtions of mitochondria

Answer 5

1. Production of energy
2. Generation of reactive oxygen species (lack may lead to cell death)
3. Integration of apoptosis signaling (lack of which may lead to premature cell death)

Question 6

What features make up the physical structure of mitochondrial DNA?

Answer 6

• Double stranded and circular
• 37 genes encoded (totally sequenced)
• Independent transcription of both strands in mitochondria
• No Introns
• More than 100 point mutations and more than -100 rearrangements associated with disorders

Question 7

What are the genetic components of the OXPHOS complex subunits?

Answer 7

Complex I (7)
Complex II (0)
Complex III (1)
Complex IV (3)
Complex V (2)
tRNA genes (22)
rRNA genes (2)

mtDNA in parentheses

Note: All complexes have contributions from nDNA and only complex II has no contribution from mtDNA

Question 8

From whom do you receive your mitochondria?

Answer 8

Mother

Question 9

Does mitochondrial DNA have a higher mutation rate than nuclear DNA?

Answer 9

Yes. (~10X) This increases chance of disease occurance

Question 10

Where is abnormal expression of mtDNA detected most often and why?

Answer 10

Brain, muscle, heart, kidney, etc.

Seen here because these tissues/organs have high ATP requirements

Question 11

What is homoplasmy?

Answer 11

Single cell - only one type of mtDNA sequence in the mit population in the cell

Can be either wild type mtDNA or mutant mtDNA

Question 12

How does mitochondrial genetics relate to the nuclear genome?

Answer 12

Autosomal disorders (AR/AD) similar to mit-genome disorders

Nuclear genes are required for integrity of normal structure and number of mtDNA

Question 13

What is heteroplasmy?

Answer 13

Single cell with mixed population of mtDNA at a locus - normal mt-genome genotype and mutant mt-genome genotype(s)

Question 14

Is heteroplasmy a type of mosaicism?

Answer 14

No

Question 15

Are the levels of cellular heteroplasmy the same in all cells?

Answer 15

No can vary from cell to cell and tissue to tissue

Question 16

What are some requirements for expression of a disease in an individual with heteroplasmy?

Answer 16

Must reach threshold expression

Question 17

What is the sequence of events for replicative segratation

Answer 17

1. Start with one cell with heteroplasmy
2. Repeated cell divisions
3. Repeated replications of mt genome
4. Random drift (different proportion of mt genome, either mutant or normal, go into each daughter cell)
5. Percent of abnormal mutant mt in each cell wil generally determine the function of that cell (ie 60-70% of mutant mt genome required for deleterious expression)

Question 18

What is threshold expression?

Answer 18

The percentage of mutant mtDNA needed in a cell to show the disease

Question 19

Can both males and females be affected by mitchondrial disorders if their mother has disorders?

Answer 19

Yes, both inherit the mtDNA from their mother

Question 20

Are all affected individuals homoplasmic?

Answer 20

No, they can be either homoplasmic or be heteroplasmic with enough mutant mtDNA to surpass threshold levels

Question 21

Are all unaffected individuals heteroplasmic?

Answer 21

No, hey can be either homoplasmic or be heteroplasmic without enough mutant mtDNA leaving them below the threshold level.

Question 22

What types of mutations are seen in mtDNA?

Answer 22

Point mutations and insertions/deletions

Question 23

What things do mitochondrial diseases exhibit?

Answer 23

Reduced penetrance, variable expression, and pleiotropy

Question 24

What is the estimate of people with a mitochondrial disorder?

Answer 24

1/10,000 - 1/20,000

Question 25

What are some examples of mitochondrial dieseases?

Answer 25

Leber’s Hereditary Optic Neuropathy
Kearn’s Sayre Syndrome
MERRF
MELAS

Question 26

What is Leber’s associated with?

Answer 26

Optic nerve atrophy

It is usually homoplasmic

Question 27

How do individuals acquire MERRF and MELAS?

Answer 27

They have a single base change in tRNA genes

Question 28

What are the goals of treatment for mitochondrial disorders?

Answer 28

Slow progression
Alleviate symptoms
(No cure)

Question 29

What do some of the general treatments for mitochondrial disorders do?

Answer 29

Prevent acute decompensation, and they provide or replace deficient metabolites