myocardial myopathies Flashcards
describe mitochondrial DNA? 4
- 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
describe the origins of the mitochondrion? 3
- 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
describe maternal inheritance of mitochondria? 3
- 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
describe the mitochondrial genome? 6
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
describe the mitochondria and ageing? 3
- 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
describe defects in OXPHOS? 4
- Involve tissue most reliant in OXPHOS
- Occur later in age
- Progressive with age
- Shows progressive enrichment in mutated mtDNAs
name some reactive oxygen species? 5
- Superoxide anion (O2-)
- Hydroxyl radical (HO)
- Peroxide ion (O22-)
- Hydrogen peroxide (H2O2)
- Hypochlorous acid (HOCl)
describe the generation of ROS in the mitochondrion? 2
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
describe the efficiency of OXPHOS with ROS? 3
- 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
what are mitochondrial diseases? 4
- 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)
describe the biochemical classification of mitochondrial diseases? 5
- 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)
what are mitochondrial myopathies? 5
- 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
describe the heterogeneity of mitochondrial disease? 3
- Onset of symptoms, phenotypic variability and variable penetrance of mt diseases are governed by:
- Homoplasmy and heteroplasmy of mt threshold effect
- Mt genetic bottleneck
describe the mitochondrial threshold effect? 3
- 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
describe the mitochondrial genetic bottleneck? 3
- 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
name 4 mitochondrial myopathies caused by mutations in the mitochondrial DNA?
- 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
describe LHON syndrome? 5
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
describe MERRF syndrome? 7
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)
describe MELAS syndrome? 9
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
describe KSS? 9
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
how are mitochondrial myopathies diagnosed?
combination of biochemical tests, histology and genetic
what is the prognosis for mitochondrial myopathies?
variable and dependent on the type of disease and patient’s metabolism
name two types of therapy for people with mitochondrial myopathies?
- Occupational/ physical therapy may extend the range of muscle movement
- Vitamin therapies such as riboflavin, creatine and carnitine may improve function for some
what is the treatment for people with mitochondrial myopathies?
- No specific treatments. Development of genetic strategies’ for manipulating the mt genome
how can we prevent mitochondrial myopathies? 3
- 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
name two IVF strategies?
- 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)
