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Genomics > The Mitochondrial Genome > Flashcards

The Mitochondrial Genome Flashcards

1
Q

How do mitochondria convert energy?

A

Mitochondrial energy conversion: generation of ATP by oxidative phosphorylation (OXPHOS)

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2
Q

What is the significance of mitochondria?

A

Mitochondria are important for ATP synthesis

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3
Q

How do mitochondria generate ATP?

A

Energy stored in nutrients (Carbohydrates, lipids and proteins) is broken down and reducing equivalents used to produce ATP

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4
Q

What are the other roles of mitochondria other than energy conversion?

A

Mitochondria also produce other substances and have many other functions e.g:

  • Haem synthesis
  • Neurotransmitter synthesis, e.g. glutamate
  • Nucleotide synthesis
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5
Q

What is the layout of mtDNA

A

Double stranded circular molecule (16.6kb) (15,000x smaller than chromosome 1)

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6
Q

What are the various subunits making up the mtDNA?

A 
Consists of the heavy and light strand
Multicopy genome (10-100,000 copies per cell)
37 genes
13 oxidative phosphorylation protein subunits 
22 transfer RNAs
2 ribosomal RNAs
No introns
D-loop
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7
Q

What is the D loop in mtDNA?

A

non coding region where replication & transcription are initiated

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8
Q

How is mtDNA inherited?

A

Maternally inherited, no recombination

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9
Q

What is the role of mtDNA?

A

The Mitochondrial genome encodes proteins of oxidative phosphorylation

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10
Q

How many enzymes form the mtDNA OXPHOS complex?

A

OXPHOS consists of five enzyme complexes CI-CV in the inner mitochondrial membrane
only 13 proteins required for OXPHOS are encoded by mtDNA. More than 100 are needed

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11
Q

How many mtDNA proteins are produced for OXPHOS?

A

Mitochondria are required to produce 13 proteins of OXPHOS

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12
Q

Describe the 5 mtDNA complexes of OXPHOS

A

The first four complexes are the respiratory chain (RC) complexes (CI-CIV) and CV is the ATP synthase enzyme

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13
Q

How do the mtDNA protein complexes aid OXPHOS?

A

Three of the RC complexes pump protons across the membrane generating electrochemical potential across the membrane. This potential is then utilized by CV to produce ATP
This is known as chemiosmosis

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14
Q

What is the role of non coding regions in mtDNA

A

Non-coding region (NCR) contains regulatory sequences for replication and transcription

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15
Q

Where does mtDNA replication begin?

A

mtDNA replication starts in Origin of heavy strand (OH)

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16
Q

Where does mtDNA transcription start?

A

Transcription starts at Heavy strand promoter (HSP)

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17
Q

What is the LSP?

A

Light strand promoter (LSP)

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18
Q

What are nucleoids?

A

mtDNA is packaged into structures called nucleoids

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19
Q

How many copies of mtDNA are present in nucleoids?

A

One or two copies of mtDNA per nucleoid

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20
Q

What is the role of TFAM?

A

Transcription factor A (TFAM) acts as histone protein

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21
Q

What is a nucleoid?

A

An irregularly shaped region within the cell of a prokaryote that contains all or most of the genetic material, called genophore.

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22
Q

How do nucleoids differ from eukaryotic cell nuclei?

A

In contrast to the nucleus of a eukaryotic cell, it is not surrounded by a nuclear membrane

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23
Q

How does mtDNA differ from other DNA following the universal genetic code

A

AUA and AUG code for methionine (AUA codes for isoleucine in nuclear DNA)
UGA codes for tryptophan (stop codon in nuclear DNA)
AGA and AGG are stop codons (not arginine)

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24
Q

How does mtDNA contribute to haplogroups?

A

As mtDNA is maternally inherited different variants are restricted to different ethnic groups
mtDNA does not recombine and mutations acquired over time subdivide the human population into discrete haplogroups

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25
Q

What is a haplogroup?

A

A genetic population group of people who share a common ancestor on the patriline or the matriline

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26
Q

What is the significance of haplogroups?

A

This is used by population geneticists to track migration of human populations
Major hapolgroups arose 40,000 – 200,000 years ago

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27
Q

What is the Endosymbiotic Theory of mt Origin?

A
  1. Approximately two billion years ago bacteria colonised
    Earth - no complex multicellular life
  2. Some primitive eukaryotic organisms with nucleus’
    existed
  3. Based on phylogenetic studies, tracing evolutionary
    ancestry of organisms through their DNA shows a
    primitive eukaryotic cell ingested a bacterium
  4. The bacterium survived and two organisms benefited
    through a symbiotic relationship
  5. The bacterium evolved into mitochondria
  6. Most bacterium genes in animals have been transferred
    `to the host nucleus but a few have been retained
28
Q

What processes must mtDNA undergo to produce the 13 OXPHOS proteins?

A

To make the 13 OXPHOS proteins mtDNA must be:
Replicated
Transcribed
Translated

29
Q

How are genes encoded for mtDNA?

A

All proteins involved in replication, transcription and translation of mtDNA are encoded by nuclear genes and imported into mitochondria

30
Q

How are other proteins required for OXPHOS produced?

A

In total >1000 mitochondria but only 13 made by mtDNA, all others made by nuclear genes

31
Q

What enzymes are required for mtDNA replication?

A

Polymerase gamma (POLG)

TWINKLE

Single stranded binding protein (SSBP)

TFAM

32
Q

What is Polymerase gamma (POLG)?

A

mtDNA DNA polymerase

33
Q

What is TWINKLE?

A

Unwinds double stranded mtDNA template to allow replication by Polγ

34
Q

What is the role of Single stranded binding protein (SSBP)?

A 
Keep DNA unwound 
Binds to single stranded DNA
Protects against nucleases
Prevents secondary structure formation
Enhances mtDNA synthesis by stimulating TWINKLE helicase activity
35
Q

What is the role of TFAM?

A

packages and protects mtDNA

36
Q

What other enxymes are required for mtDNA replication?

A

In addition other proteins are needed e.g. enzymes important for making dTNTPs, the building blocks for DNA

37
Q

Describe the structure of MtDNA polymerase

A

> Polymerase gamma (Polγ) is a Heterotrimer protein

  • One catalytic subunit (POLγA)
  • Two accessory subunits (POLγB)
38
Q

What is the role of the polyA subunit of mtDNA Pol?

A

POLγA contain 3’ – 5’ exonuclease domain to proofread newly synthesized DNA

39
Q

What is the function of the PolyB mtDNA Subunit?

A

POLγB enhances interactions with DNA template and increases activity and processivity of POLγA

40
Q

Describe the structure of TWINKLE

A

TWINKLE is a Hexamer – six TWINKLE subunits

41
Q

What is strand displacement?

A

Strand displacement model is the major mode of mtDNA replication

42
Q

Outline the first step of strand displacement

A

Step 1
Parental heavy strand displaced and coated with mtSSBP
TWINKLE helicase unwinds mtDNA
Mitochondrial Polymerase (POLRMT) synthesizes RNA primer using light strand as template
POLγ uses RNA primer to replicate DNA at OH

43
Q

How does heavy strand replication occur in the 2nd step of strand displacement

A

Step 2
Heavy strand replication passes OL
Stem loop structure is formed preventing mtSSBP binding
Mitochondrial Polymerase (POLRMT) synthesizes RNA primer using heavy strand as template
POLγ uses RNA primer to replicate light strand DNA at OL

44
Q

How long does replication of mtDNA occur?

A

Synthesis proceeds until both strands are fully replicated

45
Q

What is the final syep of strand displacement of mtDNA?

A

After replication daughter molecules are segregated

46
Q

Why are mtDNA strands named “heavy” and “light”?

A

The heavy strand is guanine-rich and encodes for 28 genes

The light strand is cytosine-rich and encodes for 9 genes

47
Q

What is a rare monogenix disease?

A

Rare monogenic diseases
A disease is defined as rare when it affects less than 1:2000 individuals

Typically, these disorders are progressive; still no curative treatments

48
Q

Which tissues/organs does mt disease affect?

A

Affect highly metabolic organs

Abundant in mitochondria

49
Q

What are the effects of mt disease?

A

Wide disease spectrum e.g.

  • Hearing loss
  • Fatal cardiomyopathy in infancy
50
Q

Which systems are typically affected by mt disease?

A

Cns
muscles
the heart
metabolic syndromes are also common

51
Q

What are the symptoms of mt disease?

A

Can also cause isolated symptoms such as hearing loss
However, in many patients, the clinical symptoms might be non-specific and mitochondrial disease is only one of several possible diagnoses

52
Q

How many mt disease genes are there?

A

> 300 mitochondrial disease genes

53
Q

How are mt disease genes inherited?

A

Primary mtDNA mutations
Passed on maternally
mtDNA mutations cause many different diseases
Common variants in mtDNA can contribute to the development of complex diseases

54
Q

Other than mtDNA mutations, how else is my disease inherited?

A

Nuclear mutations in >300 nuclear genes cause mitochondrial disease.
Not just mtDNA

55
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

56
Q

What is the composition of mtDNA in healthy cells?

A

Cells can contain pure (homoplasmy) or mixed (heteroplasmy) populations of mtDNA molecules

57
Q

Describe the composition of genome in mtDNA diseases

A

For mtDNA diseases usually minimum amount of mutation is required for diseases manifestation >80%

58
Q

In what order are mtDNA mutations inherited?

A

Inheritance of mutation load is random

Mitochondria are inherited solely through the maternal line. So mitochondrial DNA diseases show maternal inheritance

59
Q

How are mtDNA mutations identified?

A 
mtDNA mutations can be identified by next-generation sequencing (NGS)
Mutation load (‘heteroplasmy’) can be accurately quantified with NGS
60
Q

How can we avoid myDNA disease inheritance?

A

Mitochondrial replacement therapy for mtDNA disease (‘Three-parent babies’)

61
Q

Explain how 3 parent babies are produced

A

1, Healthy nuclear DNA removed from patients egg cell
(faulty mtDNA left behind)

2, Patients nuclear DNA transplanted in donor w egg with
healthy mtDNA

3, reconstructed egg cell fertilised with sperm in lab and
implanted into patient

62
Q

How do secondary mtDNA mutations arise?

A

Mutations in mtDNA replication machinery cause secondary mutations in mtDNA
mtDNA deletions
mtDNA depletion

63
Q

Where do secondary mtDNA mutations occur?

A

Occurs in post-mitotic tissues

  • Brain
  • Muscle
  • Heart
  • Liver
64
Q

What is the result of TWINKLE mutations?

A

Dominant mutations in TWINKLE cause mtDNA deletions and late-onset mitochondrial myopathy

65
Q

What is the effect of dominant TWINKLE mutations?

A

Multiple mtDNA deletions in muscle, brain and heart

Progressive external ophthalmoplegia (PEO), muscle weakness, exercise intolerance

66
Q

Why is there no cure / treatment for TWINKLE mutations?

A

No cure and lack of treatments
Lack of biomarkers for diagnosis and as outcome measures in clinical trials
Reasons for tissue-specificity unknown

Genomics (20 decks)

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