Mitochondrial myopathies Flashcards
Origins of the mitochondrion
Endosymbiotic relationship
Many features of mitochondrial DNA 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
Mitochondrial DNA
Closed circular double stranded molecule
5-10 copies of the genome in each mitochondrion
Human mitochondrion genome is 16.5kb
> 900 different mt proteins are encoded by nDNA o cytosolic ribosomes, important and then assembled in the mitochondrion
Maternal inheritance
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 the egg are destroyed
Mitochondrial genome
Many of the genes needed for mitochondrial function have moved from the mitochondrion into nuclear genome
Mt genome codes for:
13 of the respiratory chain proteins
2 rRNA
22 tRNA
Mutation of mt DNA
Respiratory chain is the major producer of ROS
Mt genome suffers the greatest exposure to and damage by ROS
mtDNA less effective at correcting mistakes and repairing mt DNA damage
Defects in mtDNA accumulate with age and mtDNA mutates more rapidly than nDNA
Reactive oxygen species
Superoxide anion
Hydroxyl radical
Peroxide ion
Hydrogen peroxide
Hypochlorous acid
Efficiency of OXPHOS
Efficiency declines with age as a result of accumulation of mutation s to mtDNA due to ROS
OXPHOS enzyme defects strongly implicated in Alzheimer’s/ Parkinsion’s type II diabetes
Defects in OXPHOS
Involve tissues most reliant on OXPHOS
Occurs later in life
Progressive with age
Show progressive enrichment in mutated mtDNA’s
Mitochondrial diseases
Arise from defects in mt enzymes and systems
Major defects are incompatible with life and affect embryos very rarely survive
Over 150 different mitochondrial diseases, some linked to mtDNA
Often involve CNS and musculoskeletal system
Mitochondrial myopathies
Number of human diseases attributed to mutations in mt genes in mtDNA, reduce capacity of cells to produce ATP
Some tissues/ cell types less able to tolerate lowered ATP production
Group of neuromuscular disease
Most occur before the age of 20, beginning with exercise intolerance or muscle weakness
Other symptoms
- heart failure/ rhythm disturbances
- dementia
- deafness
- blindness
- seizures
Clinical features of mitochondrial diseases
Onset of symptoms, phenotypic variability and variable penetrance of mt diseases governed by:
- homoplasmy and heteroplasmy of mt
- mt genetic bottleneck
Threshold effect
At cell division, mitochondria are distributed unequally and do not necessarily reflect the ration found in the progenitor cell
Above threshold causes disease
Mt myopathies- biochemical classification
- Defects of mitochondrial transport systems
- Defects of substrate utilisation
- Defects of TCA cycle
- Defects of OCPHOS coupling
- Defects of oxidative phosphorylation
Defects of mitochondrial transport systems
Carnitine palmitoyltransferase (CPT I and II) deficiencies
Defects of substrate utilisation
Pyruvate dehydrogenase complex deficiency
Fatty acid oxidation defects
Defects of TCA cycle
Fumarase deficiency
or
Alpha ketoglutarate dehydrogenase deficiency
Defects of OXPHOS coupling
Luft’s syndrome
Defects of oxidative phosphorylation
Complexes I/II/III/IV/V deficiencies combined defects of respiratory chain components
LHON
Lebers hereditary optic neuropathy
Single base change in mt gene ND4 (from Arg to His) in a polypeptide of complex I
Mt partially defective in e- transport from NADH to UQ
Not sufficient ATP produced to support neurones
Damage to optic nerve- blindness
Also causes by single base change in mt gene for cyt b in complex III
MERRF
Myoclonus epilepsy with ragged red fibres
Caused by point mutation in mt gene encoding tRNA specific for lysine
Disrupts synthesis of proteins essential for oxidative phosphorylation
Caused by a mutation at position 8344 in mt genome in over 80% cases
Skeletal muscle fibres of MERRF patients have abnormally shaped mitochondria
MELAS
Mitochondrial enxephalomyopathy lactic acidosis and stroke like episodes
Affect primarily the brain and skeletal muscle
Mt gene dysfunction involving mt ND5 (complex I) and mt-TH, mt-TL1 and mt-TV
Symptoms appear later in childhood
- build up of lactic acid
- stroke like episodes with muscle weakness, seizures, loss of visions, movement difficulties
- dementia
KSS
Kearns-Sayre syndrome
Results from 5kb deletion of mt genome
Onset before age 20
Short stature and multiple endocrinopathies including diabetes
Dementia and retinitis pigmentosa
Lactic acidosis, heart conduction defects, raised cerebrospinal fluid protein content
Ragged red fibres
Clumps of defective mitochondria accumulate in aerobic skeletal muscle fibres
Appear red after staining with Gomori modified Trichrome
Associated with mitochondrial disease
Retinitis pigmentosa
Group of genetic eye conditions where abnormalities of rods and cones or retinal pigment epithelium of the retina lead eventually to blindness
Mitochondrial myopathies prognosis
Variable and dependent on the type of disease and the patient’s metabolism
Varies greatly between individuals
Occupational/ physical treatment
May extend the range of muscle movement
Vitamin therapies
Riboflavin, creatine, CoQ, C, K and carnitine may improve function for some
IVF strategy
Designed to replace defective mitochondria inherited from a mother
Merging DNA from two fertilised eggs- mother with defective mt, other from healthy donor
Malfunctioning mitochondria are replaced by donor healthy ones
