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104 Theme 2 - Liver and Metabolism > Mitochondrial myopathies > Flashcards

Mitochondrial myopathies Flashcards

1
Q

What is the structure of mitochondrial DNA?

A
  • closed circular double stranded molecule
  • Human mt genome is 16.5 kb
  • 5 -10 copies of the genome in each mitochondrion (a cell has 2 - 2000 mitochondria)
  • > 900 different mt proteins are encoded by nDNA, translated on cytosolic ribosomes, imported and then assembled in the mitochondrion
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2
Q

What does “ ENDOSYMBIOTIC ORIGIN “ mean?

A
  • Many features (circular DNA / 70S ribosomes) of the mt genetic system resemble those found in prokaryotes
  • Strengthened the theory that mitochondria are the evolutionary descendants of a prokaryote
  • Result of an endosymbiotic relationship with ancestral eukaryotic cells early in the history of life on earth
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3
Q

How does maternal inheritance work?

A
  • The embryo essentially derives all its mitochondria from the egg
  • Most sperm mitochondria are in the tail - not absorbed on fertilisation

Any paternal mitochondria that do enter egg are destroyed

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4
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5
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6
Q

What does the mitochondrial genome code for?

A

•Many of the genes needed for mitochondrial function have moved from the mitochondrion into the nuclear genome over evolutionary time

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7
Q

Label the diagram

A
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8
Q

What effect does ageing have on mitochondria?

A

ØEfficiency declines with age

ØPartly as a result of the accumulation of damage and mutations to mtDNA caused by ROS

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9
Q

What conditions are associated with OXPHOS defects?

A

ØDefects in OXPHOS are strongly implicated in Alzheimer’s/Parkinson’s and type II diabetes

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10
Q

What are OXPHOS defects?

A
  • involve tissues most reliant on OXPHOS
  • occurs later in life
  • progressive with age
  • show progressive enrichment in mutated mtDNA’s
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11
Q

What are redox reactions?

A

Reduction-oxidation reactions are essential for cell metabolism

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12
Q

Write an equation for the reduction of oxygen

A
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13
Q

Name the reactive oxygen species (ROS)

A

Superoxide anion (O2.-)

Hydroxyl radical (HO.)

Peroxide ion (O22-)

Hydrogen peroxide (H2O2)

Hypochlorous acid (HOCl)

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14
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15
Q

How does the efficiency of OXPHOS change with aging?

A
  • Respiratory chain is the major producer of reactive oxygen species (ROS)
  • mt genome suffers the greatest exposure to, and damage by, ROS
  • mt DNA less effective at correcting mistakes and repairing mt DNA damage
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16
Q

What are mitochondrial diseases?

A

ØDiseases arising from defects in mt enzymes and systems e.g. in the TCA cycle and OXPHOS are rare

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17
Q

What is the effects of mitochondrial diseases?

A

ØMajor defects are incompatible with life and affected embryos very rarely survive

ØNevertheless there are over 150 different mitochondrial diseases and some are linked to mtDNA

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18
Q

What are mitochondrial myopathies?

A

ØMitochondrial diseases often involve CNS and musculoskeletal system (also known as mitochondrial myopathies)

•Group of neuromuscular diseases

19
Q

What are the 5 biochemical classifications of mitochondrial disease?

A
  1. Defects of mitochondrial transport systems

Carnitine palmitoyltransferase (CPT I and II) deficiencies

  1. Defects of substrate utilisation

Pyruvate dehydrogenase complex (PDC) deficiency

Fatty acid oxidation defects

  1. Defects of TCA cycle

Fumarase deficiency OR a- ketoglutarate dehydrogenase deficiency

  1. Defects of OXPHOS coupling

Luft’s syndrome

  1. Defects of oxidative phosphorylation

Complex I / II / III / IV / V deficiencies (defects of respiratory chain components)

20
Q

Why are the majority of mitochondrial diseases mitochondrial myopathies?

A

A number of human diseases are attributed to mutations in mt genes in mtDNA that reduce the capacity of cells to produce ATP

Some tissues / cell types e.g. neurons, myocytes, skeletal muscle cells and the b-cells of the pancreas are less able to tolerate lowered ATP production

21
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22
Q

What are the symptoms of mitochondrial myopathies and when do they arise?

A
  • Most occur before the age of 20, often beginning with exercise intolerance or muscle weakness
  • Other symptoms include heart failure / rhythm disturbances, dementia, deafness, blindness and seizures
23
Q

Onset of clinical symptoms, phenotypic variability, and variable penetrance of mt diseases are governed by…

A
  • Homoplasmy and heteroplasmy of mt - threshold effect
  • Mt genetic bottleneck
24
Q

What is the threshold effect?

A
25
Q

What is the mitochodrial genetic bottleneck?

A
26
Q

Name the Mt myopathies caused by mutations in mtDNA

A

LHON - Lebers hereditary optic neuropathy

MERRF - myoclonus epilepsy with ragged-red fibre

MELAS - mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes

KSS - Kearns-Sayre syndrome

27
Q

What is the genetics of LHON syndrome?

A
  • Single base change in the mt gene ND4, (from Arg to His) in a polypeptide of Complex I
  • A single base change in the mt gene for cyt b in complex III also produces LHON
28
Q

What causes LHON syndrome?

A
  • Mitochondria partially defective in e- transport from NADH to ubiquinone
  • Some ATP produced by e- transport from succinate, but not enough to support the very active metabolism of neurons
29
Q

What are the symptoms of LHON syndrome?

A

•Results in damage to the optic nerve and leads to blindness

30
Q

What are the genetics of MERRF syndrome?

A
  • Caused by a point mutation in the mt gene encoding a tRNA specific for lysine (tRNALys)
  • MERRF syndrome is caused by a mutation at position 8344 in the mt genome in over 80% of cases
  • Many other genes are involved and include:

mt – TK, mt - TL1, mt – TH, mt – TF

31
Q

What causes MERRF syndrome?

A
  • Disrupts synthesis of proteins essential for oxidative phosphorylation (ATP synthesis)
  • Skeletal muscle fibres of MERRF patients have abnormally shaped mitochondria
32
Q

Whats the diagnosis?

A

MERRF syndrome

Ragged red fibres

33
Q

What are ragged red fibres?

A

Clumps of defective mitochondria accumulate in aerobic skeletal muscle fibres (appear red after staining with Gomori modified Trichrome)

Associated with mitochondrial disease

34
Q

What are the symptoms of MELAS syndrome?

A

Mt myopathy affecting primarily the brain and skeletal muscle

Symptoms appear in childhood and include: build-up of lactic acid (lactic acidosis), stroke-like episodes with muscle weakness, seizures leading to loss of vision, movement difficulties (incl. involuntary muscle spasms (myoclonus) and dementia

35
Q

What are the genetics of MELAS syndrome?

A

•mt gene dysfunction involving mt ND5 (complex I) and mt-TH, mt-TL1 and mt-TV (all involved with tRNA)

36
Q

What are the genetics of Kearns-Sayre syndrome (KSS)?

A

Results from a 5kb deletion of the mt genome

37
Q

What are the symptoms of KSS and when is the onset?

A
  • Onset before age 20
  • Affected patients have short stature and often have multiple endocrinopathies including diabetes
  • Symptoms include dementia & retinitis pigmentosa
  • Other symptoms include lactic acidosis, heart conduction defects and raised cerebrospinal fluid protein content
38
Q

How are mitochondrial mypopathies diagnosed?

A

•Diagnosis: combination of biochemical tests, histology & genetic testing

39
Q

What is the prognosis of mitochondrial myopathies?

A

•Prognosis: variable and dependent on the type of disease and the patient’s metabolism (varies greatly between individuals

40
Q

What is the treatment for mitochondrial myopathies?

A
  • No specific treatments. Development of genetic strategies for manipulating the mt genome
  • Occupational / physical therapy may extend the range of muscle movement. Vitamin therapies such as riboflavin, creatine, CoQ, C, K and carnitine may improve function for some
41
Q

How are mitochondrial myopathies prevented?

A
  • IVF strategy designed to replace defective mitochondria inherited from a mother
  • Malfunctioning mitochondria are replaced by the donor healthy ones
  • Strategy involves merging DNA from two eggs - one from the mother with defective mitochondria, the other from a healthy donor with functioning mitochondria
  • Approved by UK parliament in February 2015
  • First licence approved in March 2017
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104 Theme 2 - Liver and Metabolism (15 decks)

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