Mitochondrial Myopathies Flashcards
Origins of the mitochondrion:
- Endosymbiotic origin
- circular DNA/70s ribosomes in
mitochondria are also found in prokaryotes - evolutionary descendants
- result of an endosymbiotic relationship
with ancestral eukaryotic cells
Mitochondrial Inheritance:
- the embryo derives all its mitochondria
from the egg - most sperm mitochondria are located in
the tail and hence not absorbed upon
fertilisation - any paternal mitochondria that do enter
the egg are destroyed
How many different mitochondrial proteins are encoded by nuclear DNA on cytosolic ribsomes, imported and then assembled in the mitochondrion?
Over 900
How many copies of the genome are there in each mitochondrion?
5 - 10 copies
Mitochondrial Genome
- many genes needed for mitochondrial
function have moved from mitochondrion
into nuclear genome - mt genome codes for:
- 13 respiratory chain proteins
- 2 rRNA
- 22 tRNA
- mt genetic code differs from the normal
universal genetic code - tRNA structure differs from nuclear
encoded tRNA
Mitochondria and ageing:
- respiratory chain is a major producer what
damaging substances
- elaborate on effect
- respiratory chain is the major producer of
reactive oxygen species (ROS) - mt genome suffers the greatest exposure
to and damage by ROS - mt genome is less effective at correcting
mistakes and repairing mt DNA damage - consequently defects in mtDNA
accumulate with age and mt DNA mutates
more rapidly (10 x ***) than nuclear DNA
Efficiency of oxidative phosphorylation (3):
- declines with age
- ***partly as a result of the accumulation of
mutations to mtDNA caused by ROS - oxidative phosphorylation enzyme defects
are strongly implicated in Alzheimer’s,
Parkinsons and type II diabetes
Defects in oxidative phosphorylation:
- involves tissues most reliant on oxidative
phosphorylation eg muscle, brain, neurons - occurs later in life and progressive with age
-> enrichment in mutated mtDN
Mitochondrial Diseases:
- are
- mostly involve
- defects in mt enzmes and systems eg TCA
cycle and oxidative phosphorylation are
rare (most die in fetus) - most involve central nervous system and
musculoskeletal system
Mitochondrial myopathies:
- some tissuess/cells like beta cells of
pancreas and neurons are less able to
tolerate lowered ATP production
mt myopathies: group of neuromuscular diseases:
- most occur before the age of 20, with
exercise intolerance or muscle weakness
- other symptoms include heart
failure/arryhtmias/ demantia/
deafness/blindness/seizures
Heterogeneity of mitochondrial diseases:
- onset of clinical symptoms, phenotypic
variability and variable penetrance of mt
diseases are governed by (2):
- homoplasmy and heteroplasmy of mt =
threshold effect - Mt genetic bottleneck
Threshold effect for mitochondrial myopathies:
- 70% mutant will express dysfunction
(generally) - at cell division, mitochondria are
distributed unequally and do not
necessarily reflect the ratio of normal:
abnormal mitochondria found in the
progenitor cell
Heteroplasmic cell
both normal and mutant mt DNA present
Mt genetic bottleneck:
Biochemical classification of mt myopathies (5):
1) Defects of the mitochondrial transport
systems
2) Defects of substrate utilisation
3) Defects of the TCA Cycle
4) Defects of oxidative phosphorylation
coupling
5) Defects of oxidative phsophorylation
1) Defects of mitochondrial transport systems:
- Carnitine palmitoyl transferase deficiencies
2) Defects of substrate utilisation:
- pyruvate dehydrogenase complex
- fatty acid oxidation defects
3) Defects of the TCA Cycle:
- fumurase deficiency
- alpha ketoglutarate dehydrogenase
deficiency
4) Defects of oxidative phosphorylation
coupling:
- Luft’s syndrome
5) Defects of oxidative phosphorylation:
- Complexes 1,2,3,4,5 deficiences combined
defects of the respiratory chain
components
LHON stands for
- Lebers hereditary optic neuropathy
- mitochondrial myopathy
MERFF stands for
- myoclonus epilepsy with ragged red fibre
- mitochondrial myopathy
LHON Syndrome: Leber’s hereditary optic neuropathy:
- single base change in mt gene ND4 in
polypeptide of Complex 1** - **mt partially defective in e- transport
from NADH to Ubiquinone - some ATP produced by e- transport from
succinagte but not enough to support the
very active metabolism of neurons - **results in damage to optic nerve;
blindness - ** single base change in cyt b in complex III
also
MERRF Syndrome: Myoclonus epilepsy with ragged red fibre:
- caused by a point mutation in gene coding
***for tRNA lysine - disrupts synthesis of proteins essential for
oxidative phosphorylation (APT synthesis) - 80% mutation at position 8344
- skeletal fibres of MERRF pts have
**abnormally shaped mitochondria
Ragged red fibres
- ***clumps of defective mitochondria
accumulate in aerobic skelatal muscle
fibres and appear red after staining
Diagnosis of mitochondrial myopathies:
- combination of biochem tests, histology,
genetic testing - initial blood/urine metabolite analysis
(lactate) - muscle biopsy: activation of mt enzymes,
rates of oxidative phosphorylation,
substrate utilisation, ATP synthesis - genetic screening to identify mutations
Prognosis of mt myopthies:
- variable and dependent on types of
disease and pts metabolism
Treatment of mt myopthies:
- occupational therapy may extend range of
muscle movement - vitamin therapies: riboflavin, carnitine etc
may help some - no specific treatments; GENETIC STRATEGY
development
Prevention of mitochondrial myopathies:
- IVF strategy designed to replace defective
mt inherited from a mother - strategy involves merging DNA from two
eggs; one from mother with defect and
another from healthy donor - malfunction mt replaced by the donor
healthy ones - approved in 2015, 2017 first license
Mitochondrial Gene Replacement: Pronuclear Stage:
- fertilised egg with abnormal mitochondria
- pronuclei removed from abnoral zygote
and transferred to a normal donor egg
which is enucleated - zygote reconstructed with normal
mitochondria
Mitochondrial Gene Replacement: Maternal Spindle Transfer:
- unfertilised abnormal egg
- spindle and chromosomes removed
- fused into an enuclleated donor egg
- then fertilisation
