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104-theme 2-the liver and regulation of metabolism > myocardial myopathies > Flashcards

myocardial myopathies Flashcards

1
Q

describe mitochondrial DNA? 4

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

describe the origins of the mitochondrion? 3

A
  • Many features of the mt genetic system resemble those found in prokaryotes
  • Strengthened the theory that mitochondria are 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

describe maternal inheritance of mitochondria? 3

A
  • The embryo essentially derived all its mitochondria from the egg
  • Most sperm mitochondria are in the tail, not absorbed on fertilisation
  • Any paternal mitochondria that enter the egg are destroyed
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4
Q

describe the mitochondrial genome? 6

A

Mitochondrial genome has a much greater gene density and no introns compared to the nuclear genome

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

Mt genome codes for:

  • 13 of the respiratory chain proteins (complex 1 (7 subunits), complex III (1 subunit), complex IV (3 subunits), ATP synthase (2 subunits)
  • 2 rRNA
  • 22 tRNA
  • Another difference is that tRNA structure differs from nuclear tRNA
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5
Q

describe the mitochondria and ageing? 3

A
  • Efficiency declines with age
  • Partly as a result of the accumulation of damage and mutations to mtDNA caused by ROS (reactive oxygen species)
  • Defects in OXPHOS are strongly implicated in Alzheimer’s/Parkinson’s and type II diabetes
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6
Q

describe defects in OXPHOS? 4

A
  • Involve tissue most reliant in OXPHOS
  • Occur later in age
  • Progressive with age
  • Shows progressive enrichment in mutated mtDNAs
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7
Q

name some reactive oxygen species? 5

A
  • Superoxide anion (O2-)
  • Hydroxyl radical (HO)
  • Peroxide ion (O22-)
  • Hydrogen peroxide (H2O2)
  • Hypochlorous acid (HOCl)
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8
Q

describe the generation of ROS in the mitochondrion? 2

A

MnSOD is there to detoxify ROS, converting then to H2O2 which is further detoxified by catalase

They can cause damage before the cell has a change to remove them fully

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9
Q

describe the efficiency of OXPHOS with ROS? 3

A
  • Respiratory chain is the major producer of ROS
  • Mt genome suffers the greatest exposure and damage by ROS
  • Mt DNA is less effective at correcting mistakes and repairing damage
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10
Q

what are mitochondrial diseases? 4

A
  • Diseases arising from defects in mt enzymes and systems are rare
  • Major defects are incompatible with life and affected embryos rarely survive
  • There are over 150 mitochondrial diseases, and some are linked to mt DNA
  • Often involve the CNS and musculoskeletal system (mitochondrial myopathies)
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11
Q

describe the biochemical classification of mitochondrial diseases? 5

A
  • Defects in mitochondrial transport systems (carnitine palmitoytransferase (CPTI and II) deficiencies)
  • Defects of substrate utilisation (pyruvate dehydrogenase complex deficiency and fatty acid oxidation defects)
  • Defects of the TCA cycle (fumarase deficiency OR alpha-ketoglutarate dehydrogenase deficiency)
  • Defects of OXPHOS coupling (Luft’s syndrome)
  • Defects of oxidative phosphorylation (complex deficiencies)
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12
Q

what are mitochondrial myopathies? 5

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 are less able to tolerate lowered ATP production (neurons, myocytes, skeletal muscles and the beta cells of the pancreas)
  • Group of neuromuscular disease
  • Often occur before 20, beginning with exercise intolerance or muscle weakness
  • Other symptoms include heart failure, dementia, deafness, blindness and seizures
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13
Q

describe the heterogeneity of mitochondrial disease? 3

A
  • Onset of symptoms, phenotypic variability and variable penetrance of mt diseases are governed by:
  • Homoplasmy and heteroplasmy of mt threshold effect
  • Mt genetic bottleneck
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14
Q

describe the mitochondrial threshold effect? 3

A
  • progenitor cell showing heteroplasmy (some are normal, some are mutant) of mitochondria
  • at cell division, mitochondria are distributed unequally and do not necessarily reflect the ratio found in the progenitor cell
  • 70% mutant is the threshold for mitochondrial disease
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15
Q

describe the mitochondrial genetic bottleneck? 3

A
  • small number of randomly selected mitochondria go into each early egg cell with a different ratio
  • number of mitochondria increases
  • can have a high level of mutation, intermediate level and low level of mutation
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16
Q

name 4 mitochondrial myopathies caused by mutations in the mitochondrial DNA?

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
17
Q

describe LHON syndrome? 5

A

lebers hereditary optic neuropathy

  • Single base change in the mt gene ND4 (from Arg to His) in a polypeptide of complex I
  • Mitochondria partially defective in electron transport from NADH to ubiquinone
  • Some ATP produced by electron transport from succinate, but not enough to support the very active metabolism of neurons
  • Results in damage to the optic nerve and leads to blindness
  • A dingle base change in the mt gene for cytochrome b in complex III also produced LHON
18
Q

describe MERRF syndrome? 7

A

myoclonus epilepsy with ragged-red fibre

  • Caused by a point mutation in the mt gene encoding a tRNA specific for lysine
  • Disrupts the synthesis of proteins essential for oxidative phosphorylation
  • Caused by a mutation at position 8344 in the mt genome in over 80% of cases
  • Many other genes are involved
  • Skeletal muscle fibres of MERRF patients have abnormally shaped mitochondria
  • Clumps of defective mitochondria accumulate in aerobic skeletal muscle fibre (appear red after staining)
19
Q

describe MELAS syndrome? 9

A

mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes

  • Mt myopathy primarily affecting the brain and skeletal muscle
  • Mt gene dysfunction involving complex I and points involved with tRNA
  • Symptoms appear in childhood
  • Build-up of lactic acid
  • Stoke like episodes with muscle weakness
  • Seizures leading to loss of vision
  • Movement difficulties
  • Dementia
20
Q

describe KSS? 9

A

Kearns-Sayre syndrome

  • Results from a 5kb deletion in the mt genome
  • Onset before 20
  • Affected patients have short stature and often have multiple endocrinopathies
  • Dementia
  • Retinitis pigmentosa
  • Lactic acidosis
  • Heart conduction defects
  • Cerebrospinal fluid protein content
21
Q

how are mitochondrial myopathies diagnosed?

A

combination of biochemical tests, histology and genetic

22
Q

what is the prognosis for mitochondrial myopathies?

A

variable and dependent on the type of disease and patient’s metabolism

23
Q

name two types of therapy for people with mitochondrial myopathies?

A
  • Occupational/ physical therapy may extend the range of muscle movement
  • Vitamin therapies such as riboflavin, creatine and carnitine may improve function for some
24
Q

what is the treatment for people with mitochondrial myopathies?

A
  • No specific treatments. Development of genetic strategies’ for manipulating the mt genome
25
Q

how can we prevent mitochondrial myopathies? 3

A
  • IVF strategy designed to replace defective mitochondria inherited from mother
  • Malfunctioning mitochondria are replaced by donor healthy ones
  • Strategy involves merging DNA from two eggs, one from the mother with defective mitochondria, the other from a healthy donor
26
Q

name two IVF strategies?

A
  • mitochondrial gene replacement: pronuclear stage (ethical issues with this as it involves creating a donor egg and destroying it)
  • maternal spindle transfer (removes ethical issues as its uses an unfertilised egg)

104-theme 2-the liver and regulation of metabolism (19 decks)

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