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
