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Genomics > The Mitochondrial Genome > Flashcards

The Mitochondrial Genome Flashcards

1
Q

How does the mitochondria generation energy?

A

Generation of ATP by oxidative phosphorylation

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2
Q

The mitochondria produces ATP. What are some other functions?

A

Haem synthesis, Neurotransmitter synthesis, Glutamate nucleotide synthesis

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3
Q

What is ATP?

A

The energy currency of the cell

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4
Q

How is ATP produced from nutrients?

A

Energy stored in nutrients (carbohydrates, lipids and proteins) is broken down and reduced equivalents used to produce ATP.

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5
Q

Structure of the mitochondrial genome (mtDNA)

A
  • Double stranded circular molecule (16.6kb)
  • Consists of the heavy and light strand
  • Multicopy genome (10 -100,00 copies per cell)
  • 37 genes
  • No introns
  • D-loop is a non-coding region where replication and transcription are initiated
  • Maternally inherited, no recombination
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6
Q

What are the 37 genes in mitochondria?

A

13 oxidative phosphorylation protein subunits
22 tRNAs
2 rRNA - translation etc

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7
Q

What is the D-loop?

A

A non-coding region where replication and transcription are initiated.

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8
Q

What has hiNextGen sequencing shown about mtDNA?

A

It has shown that mtDNA may be inherited paternally.

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9
Q

What does the mitochondrial genome encode?

A

It encodes proteins of oxidative phosphorylation

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10
Q

How many complexes are in OXPHOS?

A

Five enzyme complexes CI-CV.

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11
Q

Which is the only complex in OXPHOS encoded by the nucleus?

A

Complex II

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12
Q

What are the respiratory chain complexes?

A

The first four complexes CI - CIV

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13
Q

What is CV?

A

It is the ATP synthase enzyme

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14
Q

How many RC complexes pump proteins across the membrane?

A

Three pump protons across the mmebrane generating an electrochemical potential

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15
Q

What utilises the electrochemical potential?

A

It is utilised by CV to produce ATP. This is known as chemiosmosis.

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16
Q

How many proteins are encoded by mtDNA for OXPHOS?

A

Only 13 proteins

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17
Q

How many proteins are needed for OXPHOS?

A

more than 100

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18
Q

What does the non-coding region contain?

A

It contains regulatory sequences for replication and transcription

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19
Q

Where does mtDNA replication start?

A

It starts in the origin of heavy strand (Oh).

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20
Q

Where does mtDNA transcription start?

A

Transcription starts at heavy strand promoter (HSP) and Light strand promoter (LSP).

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21
Q

What is mtDNA packaged into?

A

It is packaged into structures called nucleoid.

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22
Q

How many copies of mtDNA are there per nucleoid?

A

One or two copies of mtDNA per nucleoid

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23
Q

What is transcription factor A (TFAM)?

A

It acts as a histone protein that packages mtDNA as well as acts as a transcription factor.

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24
Q

Which parts of mtDNA exceptions to the “universal” genetic code?

A
  • AUA and AUG code for methionine whereas AUA codes for isoleucine in nuclear DNA
  • UGA codes for tryptophan but codes for a stop codon in nuclear DNA
  • AGA and AGG are stop codons not arginine
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25
Q

Why is mtDNA restricted to different ethnic groups

A

It is maternally inherited so different variants are restricted to different ethnic groups.

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26
Q

Why do discrete haplogroups of mtDNA form?

A

mtDNA does not recombine and mutations acquired over time subdivde the human population into discrete haplogroups.

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27
Q

How is mtDNA haplogroups used by population geneticists?

A

They track migration of human populations using this data

28
Q

How long ago did the major haplogroups of mtDNA form?

A

40,000 - 200,000 years ago

29
Q

What are the lineages of mtDNA that arose in sub-Saharan Africa?

A

L0 - L3 arose 130,000 - 200,000 years ago

30
Q

How did the M and N mtDNA haplogroups arise?

A

From L3, 65,000 - 70,000 years ago that populated the rest of the world.

31
Q

Where are the N and M mtDNA haplogroups mostly located now?

A

N is directed towards eurasia

M is directed to Asia

32
Q

What is the most common mtDNA haplogroup in europe?

A

H

33
Q

What is the endosymbiotic theory for the origin of mitochondria?

A
  • Approximately 2 billion years ago when the Earth was colonised by bacteria, there was no complex multicellular life.
  • There were primate eukaryotic organisms with a nucleus.
  • A primitive eukaryotic cell is thought to have ingested a bacterium.
  • The bacterium survive and the two organisms benefited through a symbiotic relationship. This evolved to what is now called mitochondria.
  • Most genes of the bacterium in animals have been transferred to the host nucleus but few have been retained.
34
Q

What is the endosymbiotic theory?

A

A theory that is thought to explain, the origins of mitochondria as well as chloroplasts in plants.

35
Q

What does the mitochondria require for processes such as OXPHOS? How are these made and where?

A

Mitochondria requires both nuclear and mtDNA encoded proteins. mtDNA encodes 13 proteins of OXPHOS but this process requires 100.
All proteins involved in replication, transcription and translation of mtDNA are encoded by nuclear genes and imported into mitochondria.

36
Q

What is required for mtDNA replication?

A

mtDNA replication occurs continuously in cells. To replicate mtDNA you need:

  • Polymerase gamma (POLG): mtDNA DNA polymerase
  • TWINKLE: mtDNA helicase that unwinds DNA for replication
  • Single stranded binding protein (ssBP) to keep the DNA unwound
  • TFAM: packages and protects mtDNA
37
Q

Describe the structure of poly gamma

A

It is a heterotrimer protein that requires two nuclear genes.

  • One catalytic subunit (PolyA)
  • Two accessory subunits (PolyB)
38
Q

How does PolyA proofread newly synthesised DNA?

A

It contains 3’-5’ exonuclease domain that proofreads DNA

39
Q

What is the function of PolyB?

A

It enhances interactions with DNA template and increases activity and processivity of PolyA

40
Q

What does TWINKLE do?

A

It is a helicase that forms a ring around DNA to enable it to unwind. It unwinds the ds mtDNA template to allow replication by POLy.

41
Q

Structure of TWINKLE

A

Hexamer - six TWINKLE subunits

42
Q

What does mtSSBP do?

A

It is a ss binding protein that binds to single stranded DNA and protects against nucleases, prevents secondary structure formation and enhances mtDNA synthesis by stimulating TWINKLE helicase activity.

43
Q

Where does mtDNA replication start?

A

In the non-coding region at the origin of heavy strand.

44
Q

Summarise the strand displacement model of mtDNA replication

A
  • Replication of heavy strand begins at Oh.
  • Replication of light strand begins at Ol.
  • Replication of both strands meet and complete.
  • Segragation of daugther molecules
45
Q

Describe the strand displacement model of DNA replication

A
  • The parental heavy strand is displaced and coated with mtSBP.
  • TWINKLE helicase unwinds mtDNA.
  • Mitochondrial Polymerase (POLRMT) synthesises RNA primer using light strand as template.
  • Poly uses RNA primer to replicate DNA at Oh.
  • Heavy strand replication passes Ol.
  • Stem loop structure is formed preventing mtSSBP binding.
  • Mitochondrial Polymerase (POLRMT) synthesises RNA primer using heavy strand as template.
  • Poly uses RNA primer to replicate light strand DNA at Ol.
  • Synthesis proceeds until both strands are fully replicated.
  • After replication daugther molecules are segregated.
46
Q

Why are mitochondrial diseases described as rare monogenic diseases?

A

They are defined as rare as it affects less than 1:2000 individuals.

47
Q

What do mitochondrial diseases affect?

A
  • Affect highly metabolic organs that are abundant in mitochondria
  • Can affect one or several organ systems
  • Start at any age
  • Wide disease spectrum
  • Typically, these disorders are progressive
48
Q

What are some symptoms of mitochondrial diseases?

A
  • Hearing loss (one side of the disease spectrum)

- Fatal cardiomyopathy in infancy (the other side of the spectrum)

49
Q

Children may recover from one phenotype of mitochondrial disease and later develop another. Give an example

A

In pearson syndrome, the primary manifestation is exocrine pancreatic dysfunction and megaloblastic anaemia. Surviors through infancy may later develop brain disease

50
Q

What are the treatments for mitochondrial diseases?

A

There are still no curative treatments

51
Q

How many mitochondrial disease genes are there?

A

About 300 mitochondrial disease genes

52
Q

How are mitochondrial diseases diagnosed clinically?

A

Clinically signs such as:

  • Neurodegeneration
  • Liver disease
  • Muscle weakness
  • Sensory or motor neuropathies
  • Visual impairment
  • Hearing deficit
  • Cardiomyopathy
  • Kidney dysfunction and more are looked for
53
Q

How are mitochondrial diseases identified through imaging and biochemical tests?

A
  • Hallmarks of mitochondrial disease such as brain cell death etc
  • Complex IV staining in muscle showing the deficient fibres
  • Mitochondrial Respirometry
54
Q

How can mitochondrial diseases be inherited?

A
  • Primary mtDNA mutations can be inherited maternally.

- Nuclear mutations can be inherited autosomal recessively or dominantly.

55
Q

What is homoplasmy?

A

Homoplasmy is a term used in genetics to describe a eukaryotic cell whose copies of mitochondrial DNA are all identical. In normal healthy cells, there is homoplasmy.

56
Q

What is heteroplasmy?

A

Heteroplasmy is the presence of more than one type of organellar genome (mitochondrial DNA or plastid DNA) within a cell or individual. It is an important factor in considering the severity of mitochondrial diseases.

57
Q

What is the minimum amount of mutation required for mitochondrial disease manifestation

A

80% or above

58
Q

Why is NGS used to identify mtDNA mutations?

A

The entire length of mtDNA is covered with several hundred reads. Therefore, the method is highly reliable as no region is missing compared to nuclear genome. Heteroplasmy can be accurately quantified with NGS.

59
Q

How are some mtDNA diseases treated?

A

By mitochondrial replacement therapy - “Three-parent baby”

60
Q

What do mutations in mtDNA replication machinery cause?

A

Cause secondary mutations in mtDNA. For example:

  • mtDNA deletions
  • mtDNA depletions
  • Occurs in post-mitotic tissues
    • > Brain
    • > Muscle
    • > Heart
    • > Liver
61
Q

What do dominant mutations in TWINKLE cause?

A

It causes mtDNA deletions and late-onset mitochondrial myopathy

62
Q

What is mitochondrial myopathy?

A

Multiple mtDNA deletions in muscle, brain and heart

63
Q

What are the symptoms of mitochondrial myopathy?

A
  • Progressive external opthalmoplegia (PEO), muscle weakness, exercise intolerance
64
Q

What is the cure for mitochondrial myopathy?

A

There is no cure and lack of treatments. Lack of biomarkers for diagnosis and as outcome measures in clinical trials

65
Q

What is the deletor mouse model for mitochondrial myopathy?

A

A model to investigate disease mechanism and test treatments.

66
Q

What twinkle gene causes mtDNA deletions and mitochondrial myopathy?

A
  • Twinke^(dup353-365) is a duplication mutation in humans that casues mtDNA deletions and mitochondrial myopathy

Genomics (19 decks)

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