Mito

Question 1

Roles of Mitochondria

Answer 1

1. Energy production
2. Calcium homeostasis
3. Apoptosis
4. Radical species generation
5. Radical species scavenging
6. Steroid biosynthesis
7. Orchestrate Metabolism

Question 2

Complex _ is comprised of only nuclear subunits

Answer 2

II

Question 3

Jobs of nuclear genes in mitochondria:

Answer 3

1. Structural subunits of enzyme complexes
2. Cofactors
3. Assembly factors
4. Translation factors
5. Mitochondrial DNA maintenance
6. Fission/fusion

Question 4

mtDNA

Answer 4

• Mitochondrial genome has 16,569 base pairs
• Double-stranded

mtDNA contains 37 genes:
•13 polypeptides
• Complex I: 7/45 subunits
• Complex II: 0/4 subunits
• Complex III: 1/11 subunits
• Complex IV: 3/13 subunits
• Complex V: 2/12-13 subunits

• 22 tRNAs
• 2 rRNAs (12S and 16S )

Question 5

Key features of mtDNA genome

Answer 5

• No introns
• No homologous recombination or meiosis
• Replication is continuous, not synchronized with cell cycle
• Relative to nDNA, mtDNA has a high mutation rate
• mtDNA exists in a “nucleoid” but has no histones

• Disease-causing mtDNA mutations occur in tissue-specific fashion

• Point mutations (single or few nucleotide basepairs)
• Deletions or duplications (common 5 kilobase deletion)
• Depletion or proliferation (mtDNA genome copy number change)

Question 6

Threshold effect

Answer 6

• Specific heteroplasmy load for a specific mtDNA mutation that any given tissue
tolerates before it shows signs of pathology

Question 7

Heteroplasmy vs. homoplasmy

Answer 7

• Homoplasmic wild-type: only (100%) wild-type mtDNA is present
• Homoplasmic mutant: only (100%) mutant mtDNA is present
• Heteroplasmy: 2 different populations of mtDNA are present in a given cell or
tissue (e.g. wild-type and mutant)

Question 8

RR with maternal inheritance pattern to full siblings

Answer 8

1-4% if no symptoms in
mother;

up to 50% if symptomatic
mother (EMPIRIC RISK)

Question 9

Manifestations of mito disease

Answer 9

optic neuropathy, rentinopathy and external ophthalmoplegia, deafness, stroke, ataxia, epilepsy, encephalopathy and migraines, cardiomyopathy and conduction defects, diabetes, renal failure, anemia, liver failure, intestinal pseudoobstruction and diarrhea, peripheral neuropathy, muscle weakness, exercise intolerance, cramps, atrophy, and hypotonia

Question 10

NARP

Answer 10

Neurogenic Ataxia and Retinitis Pigmentosa

Question 11

LHON

Answer 11

Leber Hereditary Optic Neuropathy

Question 12

MERFF

Answer 12

Myoclonic epilepsy with Ragged Red Fibers

Question 13

MELAS

Answer 13

Mitochondrial Encephalomyopathy, lactic acidosis, and strokes

Question 14

Low percentage heteroplasmy of MELAS (<30%)

Answer 14

Diabetes Mellitus

Question 15

Pancytopenia, symptoms improved with blood transfusion, follow up labs revealed persistent pancytopenia. Bone marrow aspiration revealed sideroblastic anemia

Answer 15

Pearson Syndrome

Question 16

Acute encephalopathy, SNHL, bilateral ptosis, regular classes with 1:1 and modified assignments, autism

Answer 16

Kearn Sayre Syndrome (KSS)

Question 17

Anemia, exocrine pancreas dysfunction, fatal in infancy, deletion detecte din blood

Answer 17

Pearson syndrome

Question 18

Retinitis pigmentosa, PEO, cardiac conduction block , increased CSF protein, cerebellar ataxia, short stature, HL, demetia, diabetes, limb weakness, hypoparathyroidism, growth hormone difficiency. Deletion detected in CNS and muscle. Childhood - young adulthood onset.

Answer 18

Kearns-Sayre Syndrome (KSS)

Question 19

Ptosis, opthalmoplegia (lose ability to move eyes laterally). Deletion detected in muscle. Young adulthood to late adulthood onset.

Answer 19

Progressive External Ophthalmoplegia (PEO)

Question 20

MtDNA deletion disorders

Answer 20

large mtDNA genome deletions (1.1 to 10 kb).

Usually de novo.

Question 21

POLG disorders

Answer 21

• Alpers-Huttenlocher syndrome (AHS)
• Childhood myocerebrohepatopathy spectrum (MCHS)
• Myoclonic epilepsy myopathy sensory ataxia (MEMSA)
• Ataxia neuropathy spectrum (ANS)

• Progressive external ophthalmoplegia (autosomal recessive or autosomal
dominant)

Question 22

Childhood-onset progressive and severe

encephalopathy with intractable epilepsy and liver failure

Answer 22

Alpers-Huttenlocher syndrome (AHS)

Question 23

Infantile or childhood
onset developmental delay or dementia, lactic acidosis, myopathy, failure to thrive,
liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss

Answer 23

Childhood myocerebrohepatopathy spectrum (MCHS)

Question 24

Epilepsy, myopathy,

and ataxia without ophthalmoplegia

Answer 24

Myoclonic epilepsy myopathy sensory ataxia (MEMSA)

Question 25

Ataxia, sensory ataxia neuropathy

dysarthria, seizures and ophthalmoplegia

Answer 25

Ataxia neuropathy spectrum (ANS)

Question 26

Progressive weakness of the extraocular eye muscles resulting in
ptosis and ophthalmoplegia , with or without generalized myopathy, variable
degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression,
Parkinsonism, hypogonadism, and cataracts

Answer 26

Progressive external ophthalmoplegia (autosomal recessive or autosomal
dominant)

Question 27

The ONLY polymerase for the mtDNA genome

Answer 27

Polymerase-γ (gamma) - POLG

Question 28

• 3 functional regions of POLG:

Answer 28

• Exonuclease: proofreading
• PEO and mtDNA deletions/point mutations
• Linker: linker between polymerase and exonuclease region
• Ataxia and mtDNA deletions
• Polymerase: replication
• Alpers syndrome and mtDNA depletion
• Seizure, dementia, regression, cortical blindness, liver disease

Question 29

Diseases with immediate onset after birth (congenital lactic acidosis) are most
likely caused by

Answer 29

autosomal recessive nDNA mutations

Question 30

Diseases with later (adult) onset are more often due to

Answer 30

mtDNA mutations

Question 31

A majority of mitochondrial disease is caused by

Answer 31

autosomal recessive inheritance

Question 32

The only proven therapy for mito disease

Answer 32

Exercise

Question 33

Four principles of maternal inheritance

Answer 33

1) Asexual, inherited from mothers only
2) Heteroplasy, co-existence of 2+ types of mtDNA in cell, tissue, or organism (mutation and tissue dependent)
3) Bottleneck: heteroplasmy can vary drastically among siblings and is unstable
4) Threshold, heteroplasmy can be tolerated to a certain limit in cells; lower threshold in tissues with high energy demands