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xGenomicss > The mitochondrial genome > Flashcards

The mitochondrial genome Flashcards

1
Q

What are mitochondrial functions?

A
  • Haem Synthesis
  • Generates ATP
  • Apoptotic cell death
  • Produces ROS
  • Important in inflammation and innate immunity, surface of antibodies contain antibodies called the mitochondrial antiviral signalling complex/ MAVs
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2
Q

What is the structure of the mitochondrial genome?

A
  • Double stranded circular molecule
  • Consists of heavy and light strand
  • Multicopy genome (10-100,000 copies per cell)
    • 37 genes
      • 13 oxphos protein subunits
      • 22 transfer RNAs
      • 2 ribosomal RNAs (required for translation of 13 encoding protein subunits)
  • No INTRONS
  • D-loop is non-coding region where replication and transcription are initiated
  • Maternally inherited, no recombination
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3
Q

What does the mitochondrial genome consist of and not have?

A

Consists of heavy and light strands and has no introns

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4
Q

How many genes does the mitochondrial genome have?

A

Has 37 genes

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5
Q

What are the genes present in the mitochondrial genome and the amount present?

A

-13 Oxidative phosphorylation protein subunits -22 tRNAs -2 rRNAs

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6
Q

What is the D loop in the mitochondrial genome?

Comment on processes and where they occur in mitochondrial DNA

A

The D loop is a non-coding region where replication and transcription are initiated

  • mtDNA replication starts in Origin of heavy strand (OH)
  • Transcription starts at Heavy strand promoter (HSP) and light strand promoter (LSP)
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7
Q

How is the mitochondrial genome inherited?

A

Maternally inherited, no recombination

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8
Q

What does the mitochondrial genome encode?

A

Encodes proteins of oxidative phosphorylation

  • There are 13 OXPHOS proteins
  • The first four are respiratory chain complexes (CI-CIV) and CV is ATP synthase
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9
Q

What does the non-coding region contain?

A

Contains regulatory sequences for replication and transcription

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10
Q

What is mtDNA packaged into?

A

Packaged into nucleoids

  • There are 1 or 2 copies of mtDNA per nucleoid
    • Transcription factor A (TFAM) acts as a histone protein
      • Prevents it from being damaged and replicated
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11
Q

Explain how mtDNA gives rise to haplotypes

A

Because mtDNA is maternally inherited it will give rise to haplotypes

Haplotypes = Group of alleles inherited together from a single parent

  • mtDNA does not recombine, and mutations acquired over time subdivide the human population into discrete haplogroups
    • This is used to track migration of human populations
    • e.g mtDNA originally had main lineages L0 to L3, these gave rise to MNN which were then taken to different parts of the world giving rise to sub haplogroups
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12
Q

What does transcription factor A(TFAM) act as when mtDNA is packaged?

A

Acts as a histone protein

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13
Q

Genetic code in vertebrate mitochondria DNA vs nuclear DNA

A

-AUA and AUG code for methionine in mitochondria; whereas in nuclear DNA, AUA codes for isoleucine -UGA codes for tryptophan in mitochondria; whereas in nuclear DNA, it’s a stop codon -AGA and AGG are stop codons in mitochondria; whereas in nuclear DNA, it’s arginine

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14
Q

What is the endosymbiotic theory of the origin of the mitochondria?

A
  • Primitive eukaryotic cell ingested a bacterium and the bacterium survived, the two organisms benefitted through a symbiotic relationship.
    • The bacterium evolved to be what we now call mitochondria
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15
Q

What does the mitochondria require both of?

A

Requires both nuclear and mtDNA encoded proteins

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16
Q

How many proteins does oxidative phosphorylation require?

A

Oxidative phosphorylation requires >100 proteins but mtDNA only encodes 13 of those proteins

17
Q

What must happen in order to make the 13 proteins for oxidative phosphorylation?

A

In order to make the 13 proteins for oxidative phosphorylation, protein mtDNA must be:

  • Replicated
  • Transcribed
  • Translated
18
Q

What are all the proteins involved in replication, transcription and translation of mtDNA encoded by?

A

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

19
Q

What are all the other proteins involved in oxidative phosphorylation made by?

A

All other proteins involved in oxidative phosphorylation are made by nuclear genes

20
Q

What do you need to replicated mtDNA?

A
  • Polymerase gamma (POLG): mtDNA DNA polymerase
  • TWINKLE: mtDNA helicase, unwinds DNA for replication
  • Single stranded binding protein (SSBP): keep DNA unwound
  • TFAM: packages and protects mtDNA
    • In addition other proteins are needed e.g. enzymes important for making dTNTPs, the building blocks for DNA.
21
Q

Describe the mtDNA polymerase

What is the function of POLgA and POLgB?

A

Called

  • Polymerase gamma (POLG)
  • Heterotrimer protein (requires two nuclear genes)
    • One catalytic subunit (POLgA)
    • Two accessory subunits (POLgB)
  • POLgA contain 3’ – 5’ exonuclease domain to proofread newly synthesized DNA
  • POLgB enhances interactions with DNA template and increases activity and processivity of POLgA.
22
Q

What does POLgammaB enhance?

A

Enhances interactions with DNA template and increases activity and processability of POLgammaA

23
Q

What is the structure of mtDNA helicase(TWINKLE)?

A

TWINKLE: -Six TWINKLE subunits

Unwinds the double stranded mtDNA template and allows replication by POLG

24
Q

What does the mitochondrial single stranded binding protein (mtSSBP) bind to and what does it do?

A

Binds to single stranded DNA

  • -Protects against nucleases
  • -Prevents secondary structure formation
  • -Enhances mtDNA synthesis by stimulating TWINKLE helicase activity
25
Q

Steps involved in the replication of mtDNA

A
  • Replication of heavy strand
  • Replication of light strand
  • Replication of both strands complete and segregation of daughter molecules occurs

Origin of the light chain allows the replication to occur in the opposite direction

26
Q

Replication of heavy strand

A
  • -Parental heavy strand displaced and coated with mtSSBP
  • -TWINKLE helicase unwinds mtDNA
  • -Mitochondrial polymerase (POLRMT) synthesizes RNA primer using light strand as template
  • -POLgamma uses RNA primer to replicate DNA at OH
27
Q

Replication of light strand

A
  • -Heavy strand replication passes OL
  • -Stem loop structure is formed preventing mtSSBP binding
  • -Mitochondrial polymerase (POLRMT) synthesizes RNA primer using heavy strand as a template
  • -POLgamma uses RNA primer to replicate light strand DNA at OL
28
Q

Completion of both strands

A

-Synthesis proceeds until both strands are fully replicated -After replication, daughter molecules are segregated by topoisomerase 3A

29
Q

Why are mtDNA strands named heavy and light strands?

A

Heavy chain has more purines which are larger than pyrimidines

30
Q

Mitochondrial diseases

A
  • Rare monogenic diseases
  • Affect highly metabolic organs
  • Can affect one or several organ systems
  • Genetically heterogeneous
31
Q

What causes mitochondrial disease?

A

Mutation in >300 nuclear genes cause mitochondrial disease, not just mtDNA

32
Q

What determines mitochondrial disease manifestation?

A

Heteroplasmy levels determine mitochondrial disease manifestation

33
Q

How is mtDNA inherited and mutation load?

A
  • mtDNA is maternally inherited
  • inheritance of mutation load is random (one individual may have a low mutation load however offspring may have a higher load)

Since we know there are nuclear genes which encode mitochondrial proteins, you will expect to see autosomal recessive patterns of inheritance of mitochondrial diseases, dominant X-linked, de novo patterns

34
Q

What way can be used to identify mtDNA mutations

A

mtDNA mutations can be identified by next generation sequencing

xGenomicss (20 decks)

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