Mitochondrial Diseases

Question 1

what do symptoms of mitochondrial diseases depend on?

Answer 1

• where mutated mtDNA is (mosacism)
• ratio of mutant to normal mitochondria (heteroplasmy)
• cell dependency on respiration

Question 2

what genes are in mitochondrial DNA

Answer 2

complexes 1, 3, 4, and 5, tRNA, and rRNA

Question 3

which complex’s gene is in the nucleus?

Answer 3

complex 2

Question 4

what does the ND mitochondrial gene code for?

Answer 4

complex 1- 7 subunits

Question 5

what does the cyt b mitochondrial gene code for?

Answer 5

complex 3- 1 subunit

Question 6

what does the CO mitochondrial gene code for?

Answer 6

complex 4- 3 subunits

Question 7

what does the ATPase mitochondria gene code for?

Answer 7

complex 5- 2 subunits

Question 8

what are the point mutations that can occur in mitochondrial chromosome that can cause disease?

Answer 8

LHON
MELAS
MERRF

Question 9

what are the general symptoms of mitochondrial disease?

Answer 9

• decreased electron transfer activity
• decreased rate of ATP synthesis
• formation of ragged red fibers (RRF)

Question 10

which complex is not affected by mitochondrial diseases?

Answer 10

complex 2- coded for by the nucleus

Question 11

what is the consequence of decreased ETC activity?

Answer 11

build up of pyruvate and fatty acids

lactate build up because of inability to do oxidative phosphorylation

Question 12

what is the consequence of decreased ATP synthesis?

Answer 12

muscle weakness and exercise intolerance

Question 13

why drives the formation of RRFs?

Answer 13

increased mitochondrial proliferation to compensate for low activity

Question 14

what signals for lactate formation?

Answer 14

increased NADH/NAD ratio from reduced ETC activity inhibits pyruvate oxidation
increase in pyruvate and NADH stimulates pyruvate reduction to lactate by lactate dehydrogenase

Question 15

what is mosacism?

Answer 15

where the mutated mitochondria end up

Question 16

what is heteroplasmy?

Answer 16

mutational load of a cell (how many mutated vs normal mitochondria there are)

Question 17

what 2 things determine the phenotype of a cell?

Answer 17

• proportion of mutant and wiltdype mtDNA present

- dependance of tissue on oxidative metabolism and energy demand

Question 18

how many normal mitochondria need to be present to maintain normal function? why?

Answer 18

small percentage

TCA cycle isn’t usually operative at Vmax, high ATP synthesis reserve that can be used

Question 19

what is threshold for impaired respiratory function?

Answer 19

50-90% mutated mtDNA

Question 20

what order are tissues affected by mutated mtDNA?

Answer 20

1. CNS
2. heart and skeletal muscles
3. renal
4. endocrine
5. liver

Question 21

what is a possible cause of mtDNA mutation? what is the evidence of it?

Answer 21

ROS damage
Evidence
- oxidized guanosine
- deletion and point mutations increase with age

Question 22

does mtDNA have a repair system?

Answer 22

no- mutations are maintained

Question 23

what are symptoms of mutations in muscle mitochondria?

Answer 23

lactic acidosis
muscle weakness (exercise intolerance)
ragged red fibers

Question 24

what are symptoms of mutations in brain and neuron mitochondria?

Answer 24

myoclonic seizures
ataxia
stroke-like episodes

Question 25

what is LHON mutation in?

Answer 25

complex 1 gene

Question 26

what is MELAS mutation in?

Answer 26

tRNA for leucine

Question 27

what are symptoms and prevalence of LHON mutations?

Answer 27

-bilateral/subacute vision failure

12/100,000

Question 28

what is MERRF mutation in?

Answer 28

tRNA for lysine

Question 29

what are symptoms of MERRF mutation?

Answer 29

myoclonus seizures
cerabellular ataxia
myopathy

Question 30

what does MERRF stand for?

Answer 30

myoclonic epilepsy with ragged red fibers

Question 31

what are symptoms of MELAS mutation?

Answer 31

recurrent headaches
vomittine
dementia

Question 32

what does MELAS stand for?

Answer 32

mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes