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PATH30001 - Mechanisms of Disease > Lecture 28 - Mitochondrial Disease 1 > Flashcards

Lecture 28 - Mitochondrial Disease 1 Flashcards

1
Q

How much ATP do we turn over every day?

A

65 kg

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2
Q

What is the surface of the mitochondrial inner membrane (all in body combined)?

A

14,000 m2 (MCG)

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3
Q

What percent of energy does our brain use?

A

20%

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4
Q

What is the generalised outcome of mitochondrial disease?

A

Any symptom, any organ or tissue, any age, any mode of inheritance

This is because mitochondria are important for every tissue in the body

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5
Q

Which is the most common mitochondrial disease of childhood?

A

Leigh disease

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6
Q

Describe Leigh disease
• Symptoms
• Age of onset
• Prognosis

A

Progressive, episodic neurodegenerative disorder

Symptoms:

Motor and / or intellectual regression

Spongiform lesions in CNS
• Demyelination
• Gliosis

Age of onset:
• 6 months of age

Prognosis:
• Death by about 3 years of age

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7
Q

What clinical consequences are seen in the ear in OXPHOS disorders?

A

• Deafness

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8
Q

What clinical consequences are seen in the eye in OXPHOS disorders?

A
  • Optical atrophy
  • Cataracts
  • Retinitis pigmentosa
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9
Q

What clinical consequences are seen in the bone marrow in OXPHOS disorders?

A
  • Myelodysplasia
  • Anaemia
  • Thrombocytopenia
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10
Q

What clinical consequences are seen in the heart in OXPHOS disorders?

A
  • Hypertrophic cardiomyopathies

* Conduction defects

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11
Q

What clinical consequences are seen in the kidneys in OXPHOS disorders?

A
  • Proximal tubuleopathy
  • Glomerulosclerosis
  • Nephropathy
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12
Q

What clinical consequences are seen in the GIT in OXPHOS disorders?

A
  • Liver failure
  • Chronic diarrhoea
  • Villous atrophy
  • Pseudo-obstruction
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13
Q

What clinical consequences are seen in the pancreas in OXPHOS disorders?

A
  • Insulin secretion defects

* Exocrine dysfunction

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14
Q

Give an overview of structure and function of mitochondria

A

Two membranes:
• Inner: protein complexes
• Outer

Function:
• Many, but most importantly energy production
• Sugar and O2 in
• ATP out

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15
Q

Indicate % of cell volume that mitochondria contribute in the following tissues:
• Fast twitch muscle fibres
• Slow twitch
• Liver

A

Fast twitch muscle fibres: 2%

Slow twitch: 8%

Liver: 20%

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16
Q

Describe the theory of the origin of mitochondria

A 
Endosymbiosis hypothesis
(Lynn Margulis)
  • Primitive aerobic bacteria was phagocytksed by a fermentating eukaryotic cell
  • Symbiosis

Evidence:
• Lipid composition in mitochondria resembles prokaryotic membrane
• Own DNA
• Encode own ribosomes
• rRNAs resemble bacterial rRNAs (ribosomal-RNAs)
• rRNAs sensitive to chloramphenicol

17
Q

How many genes do we have in the nucleus?

A

20,000

18
Q

Describe mtDNA

A

Single, ds, circular chromosome

37 genes
• Small subset of those that mitochondria actually use
• Many of the proteins are encoded by genes in the nucleus

Inherited from mother only

Encodes:
• 2 rRNA proteins
• 22tRNA proteins
• ETC complex subunits

19
Q

Which percent of proteins used by mitochondria come from mitochondrial genes?

A

5-10%

The rest come from nuclear DNA

20
Q

Compare proportion of mito disorders that are maternally inherited in:
• Child-onset
• Adult-onset

What is the mode of inheritance in these cases?

A

Child onset:
• 30%
• Mostly autosomal recessive
• Some sporadic, X-linked, autosomal dominant

Adult onset:
• 70%
• Autosomal dominant, sporadic, autosomal recessive

21
Q

Describe the genes that encode the subunits for the inner mitochondrial membrane complexes

A

Some encoded by mtDNA
Some encoded by nuclear DNA

Complex 1:
7 of 44 encoded by mtDNA

Complex 2:
All nuclear

Complex 3:
1 encoded by mtDNA

Complex 4:
3 encoded by mtDNA

Complex 5:
Couple of subunits encoded by mtDNA

22
Q

Outline the functions of the various complexes in the inner mitochondrial membrane

A

Complex 1:
Transfer of electrons to Co-enzyme Q

Complex 3 & 4:
Transfer of electrons to Co-enzyme Q to cytochrome c and then to oxygen

Complex 5:
Proton movement through pore, generation of ATP

23
Q

How many of the mitochondrial genes can have pathogenic point mutations?

Give some examples

A

35 of the 37 genes

MELAS:
• Mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes

LHON:
• Leber’s hereditary optic neuropathy

24
Q

Describe why maternal inheritance is so unusual

A

Family line of women for 9 generations:

Nuclear gene alles:
1/256th shared

mtDNA genes:
Identical

25
Q

Why is there maternal inheritance?

A

Sperm don’t contain much mitochondria

Those that they do contain are consumed by the egg

26
Q

How many copies of the mitochondrial DNA per mitochondrion?

Thus, how many copies per cell?

A

2-10 copies per mitochondrion

50-200,000 copies per cell

27
Q

Characterise the mutation rate of mtDNA

A

High mutation rate
• 10-fold higher than nuclear DNA

• This can be exploited to track human migration

28
Q

Describe heteroplasmy

A

This is the presence of more than one type of a genome

Heteroplasmy is observed for mitochondria, due to their high mutation rate

→ mutant and wild type mtDNA co-exist

29
Q

Describe the threshold of heteroplasmy

A

At some point, the amount of mutant mtDNA becomes such that the tissue is dysfunctional

This is called the threshold

< 45% mutant: 95% chance of dysfunction

NB not linear

30
Q

What is the mtDNA bottleneck?

What is the implication of this?

A

In early oogenesis, a small number of genomes are selected to repopulate the oocyte

This allows rapid shifts in heteroplasmy:
e.g.
• Small percentage of mutant mtDNA → large percentage of mutant

  1. Large number of mtDNA molecules in oocyte, one of which is mutant
  2. Rapid decrease in number: one copy of both mutant and wild-type
  3. Repopulation from the surviving mtDNA genomes: equal proportions of mutant and wild type genomes

Thus, the oocyte went from having a small percent of mutant mtDNA to a great percent of mutant mtDNA

31
Q

Describe tissue specific segregation / selection

What gives rise to this?

Give an example

A

Variation in mtDNA between tissue due to:

  • After birth: selection for or against mutations
  • Mutation load in one cell lineage increased / decreased during embryogenesis

e.g. Kearns-Sayre Syndrome
• Liver cells: 60% mutant mtDNA
• Muscle cells: 30%
• Fibroblasts: 1-2%

32
Q

Describe the process of diagnosis in individuals with mitochondrial disease

A
  1. Clinical
    • Leigh syndrome
  2. Metabolic
    • Elevated lactate in serum
  3. Histology
  4. OXPHOS enzymes
    • 20% complex 1 i.e. low
  5. DNA
    • Point mutation in mtDNA in a gene that is well known to cause disease

All these things can confirm the diagnosis
However, all the tests aren’t definitive

33
Q

Describe pronuclear transfer in humans.

When might this be used?

A

Used when mother has a mitochondrial disease or there is a high mutant mtDNA load

  1. Zygote from couple; nucleus removed
  2. Zygote form other couple; nucleus removed
  3. Nucleus from couple put into donor embryo

→ Embryo with parents nuclear DNA and healthy donor mtDNA

PATH30001 - Mechanisms of Disease (34 decks)

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