Mitochondria and associated diseases

Question 1

proteins created by mitochondrial DNA for mitochondria

proteins created by nuclear DNA for mitochondria

Answer 1

• 13
• 1700

Question 2

______ is important for import of proteins into the mitochondria. ____ in a mitochondrial protein allows it to stay in inner/outer membrane, others go to ____ through _______ channels. These proteins are then bound to _____ for refolding.

Answer 2

N-terminal “presequence” signals

Internal signals

the mitochondrial matrix

TOM/TIM

HSP 70,60

Question 3

CoA is a very large molecule with a thiol that attacks

Answer 3

acetyl

Question 4

With an electron transport disease, pyruvate increases and forms _____via _____ instead of ______ via ______. Therefore mitochondrial diseases create high _______.

Answer 4

pyruvate increases and forms lactate via lactate dehydrogenase instead of acetyl CoA and NADH via pyruvate dehydrogenase.

high NAD, lactate, pyruvate

Question 5

Charcot-Marie-Tooth (CMT) disease Type 2a

1. Mechanism
2. Symptoms
3. Diagnosis
4. MOI
5. Treatment

Answer 5

1. Defect in Mfn2 (mitofusion 2), a dynamin-like GTPase that tethers two mitochondria together for fusion). This leads to a defect in outer membrane fusion. In CMT2, there is degeneration of axons, leading to neuropathy of long peripheral nerves. Loss of motor nerves–> weakness in legs
2. Distal limb defects, steppage gait, foot deformaties
3. AD
5. No cure- PT/OT

• CMT1 is demyelinating, reduced nerve conduction + unmyelinated axons on histology. CMT2 is degenerative, unaffected nerve conduction. Histology shows myelination but no large axons.

Question 6

MFN2 role

Opa1 role

Answer 6

protein that mediates outer mitochondrial membrane fusion

mediates mitochondrial inner membrane fusion

Question 7

Autosomal Dominant Optic Atrophy (ADOA)

Answer 7

1. Opa1 (dynamin-like GTPas) results in inner membrane fusion, leading to degeneration of retinal ganglion cells, pale optic disc, enlarged blind spot
2. optic atrophy, defects in color detection early hearing loss, ptosis, ophthalmoplegia, dystaxia
3. Autosomal Dominant
4. No cure

Question 8

Kears-Searns Syndrome:

Answer 8

1. Large deletions in mitochondrial DNA including tRNAs.
2. ragged red fibers on muscle histology; anemia if defective stem cellsObligate triad: 1) onset <20 yrs, 2)progressive external ophthalmoplegia 3) pigmentary retinopathy
3. maternal (hetero-plasmy matters)
4. no cure

Question 9

Neuropathy Ataxia Retinitis Pigmentosa (NARP):

Answer 9

1. Mutation in T8993G and T899C mtDNA in 70-90% of mitochondria
2. peripheral neuropathy, pigmentary retiopathy (charateristic discoloration of retina), lactic acidosis
3. maternal (heteroplasmy matters)
4. symptom management, genetic counseling

Question 10

Maternally Inherited Leigh Syndrome (MILS)

Answer 10

1. mutation in T8993G and T899C mtDNA in > 90% of mitochondria
2. Encephalotpathy in childhood, psychomotor regression
3. Maternal (heteroplasmy matters)
4. Symptom panagement, genetic counseling

Question 11

Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)

Answer 11

1. nuclear DNA (TYMP gene) encoding mitochondrial protein thymidine phosphorylase have LOF mutations (deletions, point mutations, etc) leading to increased dTTP, dUTP which competes for dCTP. results in partial deficiency of cytochrome c oxidase.
2. Ptosis, ophthamoplegia, GI dysmotility cahexia, peripheral neuropathy, leukoencephalopathy (brain white matter diseases)
3. AR
4. bone marrow transplant supplies defective enzyme (thymidine phosphorylase)