The Mitochondrial Genome - Week 6

Question 1

The mitochondria produces

Answer 1

energy through chemical reactions - breaks down fats and carbohydrates

Question 2

The mitochondria controls

Answer 2

level of water and other materials in the cell

Question 3

Common mitochondrial disorder

Answer 3

Mutation in Maternal inherited diabetes and Deafness (MIDD)

Question 4

The mitochondria is the

Answer 4

powerhouse of the cell

Question 5

Mitochondria have their own genome. How/why?

Answer 5

o Potentially used to be bacteria before being symbiotic with humans
o They have double membrane like some bacteria, have a genome similar to bacteria – analogous structures
o Probably a different species then they became integrated in cells
o Control lots of enzymatic reactions and different levels of water within the cell

Question 6

Synthesis processes –

Answer 6

oxidative phosphorylation (ending up with ATP – essential for various enzymatic throughout the cell)

Question 7

How to visualise mitochondria within the cell

Answer 7

Need GFP (green fluorescent protein) to see mitochondria cells - hundreds of mitochondria in each cell

Question 8

• Reactions that occur on the membrane surface of mitochondria potentially leading to

Answer 8

the degeneration of ATP – used for many downstream enzyme catalysis and other processes

Question 9

Many pathogenic mutations are

Answer 9

heteroplasmic (2 or more mitochondrial DNA types)

Question 10

who do you inherit mitochondria from?

Answer 10

mother

Question 11

when do you use the term heteroplasmic?

Answer 11

• A new term used when talking about variants and mutations in mitochondria disorders often use the term heteroplasmic

Question 12

Definition of heteroplasmic

Answer 12

because of the hundreds of different mitochondria in the cell it’s possible that a mutation/variance only occurs in a small subset of the mitochondria, so you could end up with 2 or more different types of mitochondrial DNA

Question 13

homoplasmy

Answer 13

• If all the mitochondria are wild type or all are mutant

Question 14

Heteroplasmy

Answer 14

• If two or more mitochondrial DNA types

Question 15

The idea of heteroplasmy leads to a phenomonen called

Answer 15

maternal bottleneck

Question 16

Maternal bottleneck explains why mitochondrial disorders are

Answer 16

so variable in their expression (differ massively even within families)

Question 17

1. An example situation - 20% of mother’s mitochondria has mutated so mother has

Answer 17

no symptoms or mild symptoms

Question 18

2. When the early egg cell she produces come together they could have (3 options)

Answer 18

similar number of mutated mitochondria - 20% resulting in child with no disease
mutated mitochondria at around 50% = child with mild disease
mutated mitochondria at around 80% (majority) of the mitochondria might be mutated = child with severe disease

Question 19

3. Even within the same family multiple different

Answer 19

clinical presentations this is related to the fact we only inherit our mitochondria maternally

Question 20

Human mitochondrial DNA

Answer 20

multicopy - 466-806 nucleoids per cell

Question 21

Length and diameter of human mitochondrial genome

Answer 21

16,569 bp length and 0.68mM diameter (quite short)

Question 22

Mitochondrial genes lack

Answer 22

introns - they are single exon genes - so any variants are likely to have a functional effect

Question 23

Mitochondria are

Answer 23

maternally inherited

Question 24

Mitochondria were first sequenced in

Answer 24

1981 - NAture

Question 25

Mutation rate of mitochondria

Answer 25

around 1 per 33 generations (mitochondrial replication - relatively stable over time which helps with forensic analysis

Question 26

Mitochondria are

Answer 26

heteroplasmic (original and mutated forms co-exist)

Question 27

organisation of human mitochondrial DNA

Answer 27

Mitochondrial genome is circular, made up of intronless genes = 37 genes
44% GC
heavy (H) strand = G rich and the light (L) strand = C rich

28 genes have H as sense strand, 9 genes have L as sense strand

24 genes encode mature RNA
13 genes encode enzymes involved in oxidative phosphoyraltion

Question 28

how many genes in mitochondria

Answer 28

37

Question 29

heavy strands of mitochondria are

Answer 29

G rich

Question 30

Light strands of mitochondria are

Answer 30

C rich

Question 31

28 genes have

Answer 31

H as sense strand

Question 32

9 genes have

Answer 32

L as sense strand

Question 33

how many genes encode mature RNA

Answer 33

24

Question 34

how many genes encode enzymes involved in oxidative phosphorylation

Answer 34

13

Question 35

Difference between nuclear DNA and mitochondrial DNA

Answer 35

that the amino acid code in Mitochondrial DNA is slightly different i.e. UGA in universal DNA would code for a stop codon whereas in mitochondrial DNA this codes for tryptophan etc.

Question 36

Mitochondrial DNA variants causes

Answer 36

Mitochondrial encephalomyopathies

Question 37

Mitochondrial encephalomyopathies

Answer 37

• Mutations in every 20-50,000 individuals
• Clinical heterogeneity due to heteroplasmy (vast differences in presentation) but
• Mostly affects post-mitotic tissues with high oxidative demands like muscle and neuron
o Symptoms you’d see for lots of mitochondrial disorders include chronic weakness, chronic fatigue, muscle fatigue and also neurodegeneration.

Question 38

Mitochondrial disorders

Answer 38

some mitochondrial disorders are caused by point mutations

Question 39

point mutations causing mitochondrial disorders MELAS

Answer 39

o MELAS (Mitochondrial encephalomyopathy with lactic acidosis & stroke)
 general short stature, deafness and epilepsy
 Diabetes mellitus, pigmentary retinopathy and recurrent strokes.
 Mutation responsible: A-G transition at nt3243 in mt-tRNALeu(UUR) gene

Question 40

point mutations causing mitochondrial disorders - diabetes and deafness

Answer 40

o Diabetes and deafness:
 1.5% of all NIDDM (Non-insulin-dependent diabetes mellitus) mutation in 12S rRNA gene at nucleotide position 1555
 hearing loss induced after contact with aminoglycosides

Question 41

Leber hereditary optic neuropathy (LHON)

Answer 41

• ophthalmological disorder, presenting mainly in young adult males
• characterized by acute or subacute bilateral optic atrophy resulting in loss of central vision.
• > 90% of affected families have mutations at nucleotides 11778, 3460 or 14484, that encode components of complex I of the respiratory chain (very linked syndrome)
• Highly unusual in that majority of mutations present in the homoplasmic state (all of the mitochondria in the cell has the same variant)
• Also unusual is that incomplete penetrance is seen – individuals with these variants that might be in all of their mitochondria may not get the syndrome

Question 42

Mitochondrial Eve

Answer 42

• Recent African Origin Model suggests that our species evolved from a small African population that subsequently colonised the whole world
• Coalescence analysis indicates that all mtDNA in modern humans can be traced back to a single female (~100-150,000 years ago)
• Diagram shows the House of Africa Hypothesis – where different mitochondria lineages deviated over time.