Mitochondrial Diseases Flashcards
what do symptoms of mitochondrial diseases depend on?
- where mutated mtDNA is (mosacism)
- ratio of mutant to normal mitochondria (heteroplasmy)
- cell dependency on respiration
what genes are in mitochondrial DNA
complexes 1, 3, 4, and 5, tRNA, and rRNA
which complex’s gene is in the nucleus?
complex 2
what does the ND mitochondrial gene code for?
complex 1- 7 subunits
what does the cyt b mitochondrial gene code for?
complex 3- 1 subunit
what does the CO mitochondrial gene code for?
complex 4- 3 subunits
what does the ATPase mitochondria gene code for?
complex 5- 2 subunits
what are the point mutations that can occur in mitochondrial chromosome that can cause disease?
LHON
MELAS
MERRF
what are the general symptoms of mitochondrial disease?
- decreased electron transfer activity
- decreased rate of ATP synthesis
- formation of ragged red fibers (RRF)
which complex is not affected by mitochondrial diseases?
complex 2- coded for by the nucleus
what is the consequence of decreased ETC activity?
build up of pyruvate and fatty acids
lactate build up because of inability to do oxidative phosphorylation
what is the consequence of decreased ATP synthesis?
muscle weakness and exercise intolerance
why drives the formation of RRFs?
increased mitochondrial proliferation to compensate for low activity
what signals for lactate formation?
increased NADH/NAD ratio from reduced ETC activity inhibits pyruvate oxidation
increase in pyruvate and NADH stimulates pyruvate reduction to lactate by lactate dehydrogenase
what is mosacism?
where the mutated mitochondria end up
what is heteroplasmy?
mutational load of a cell (how many mutated vs normal mitochondria there are)
what 2 things determine the phenotype of a cell?
- proportion of mutant and wiltdype mtDNA present
- dependance of tissue on oxidative metabolism and energy demand
how many normal mitochondria need to be present to maintain normal function? why?
small percentage
TCA cycle isn’t usually operative at Vmax, high ATP synthesis reserve that can be used
what is threshold for impaired respiratory function?
50-90% mutated mtDNA
what order are tissues affected by mutated mtDNA?
- CNS
- heart and skeletal muscles
- renal
- endocrine
- liver
what is a possible cause of mtDNA mutation? what is the evidence of it?
ROS damage
Evidence
- oxidized guanosine
- deletion and point mutations increase with age
does mtDNA have a repair system?
no- mutations are maintained
what are symptoms of mutations in muscle mitochondria?
lactic acidosis muscle weakness (exercise intolerance) ragged red fibers
what are symptoms of mutations in brain and neuron mitochondria?
myoclonic seizures
ataxia
stroke-like episodes
what is LHON mutation in?
complex 1 gene
what is MELAS mutation in?
tRNA for leucine
what are symptoms and prevalence of LHON mutations?
-bilateral/subacute vision failure
12/100,000
what is MERRF mutation in?
tRNA for lysine
what are symptoms of MERRF mutation?
myoclonus seizures
cerabellular ataxia
myopathy
what does MERRF stand for?
myoclonic epilepsy with ragged red fibers
what are symptoms of MELAS mutation?
recurrent headaches
vomittine
dementia
what does MELAS stand for?
mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes
