Mitochondrial Disorders and Inheritance

Question 1

How many copies of the mitochondrial chromosome are present per mitochondria and per cell?

Answer 1

5-10 per mitochondria

100s-1000s per cells

Question 2

Describe the mitochondrial chromosome.

Answer 2

• Double stranded closed circle with information on both strands
• Unique genetic code
• No noncoding regions or intervening sequences
• All protein coding genes separated by tRNAs
• Mutation prone and limited repair machinery => mutation rate 5-10x nuclear DNA

Question 3

What metabolic functions occur in the mitochondria?

Answer 3

• B-oxidation
• oxidative phosphorylation
• TCA cycle

Question 4

What is the source of proteins in the mitochondria?

Answer 4

• 13 polypeptides on mtDNA

- > 1200 nuclear genes

Question 5

What are some general characteristics of mitochondrial disorders?

Answer 5

• Result from respiratory chain dysfunction
• caused by mitochondrial or nuclear gene defects
• multisystem disorders, especially affecting organs with high energy requirements (nervous system, skeletal muscle, cardiac muscle)
• highly heterogeneous expression: same mutation can have variable phenotypes

Question 6

What are some common signs of mitochondrial disease?

Answer 6

• Eyes: ptosis, external ophthalmoplegia, pigmentary retinopathy
• Muscle: myopathy, weakness, exercise intolerance
• Heart: cardiomyopathy
• Diabetes mellitus
• Central nervous system: optic atrophy, fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, spasticity

Question 7

What are some disorders caused by point mutations to mitochondrial genes?

Answer 7

• MELAS = mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes
• MERRF = myoclonic epilepsy with ragged red fibers
• NARP = neuropathy, ataxia, and retinitis pigmentosa

Question 8

MELAS

Answer 8

Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes:

• Onset in childhood
• Symptoms = seizures, recurrent headaches, vomiting, myopathy; cognitive development normal
• 80% of cases caused by a mutation to tRNA leu 1

Question 9

What are mitochondrial depletion syndromes?

Answer 9

• Autosomal recessive disorders characterized by depletion of mtRNA
• Affect brain, muscle, liver

Question 10

Kearns-Sayre syndrome/ophthalmoplegia plus

Answer 10

• Caused by deletions of mtDNA

- Phenotype is variable depending on the size of the deletion

Question 11

Alpers-Huttenlocher Syndrome

Answer 11

• Mitochondrial depletion syndrome
• Mutations to POLG (DNA pol gamma, alpha subunit) => decreased mtDNA
• Onset: childhood
• Symptoms: seizures, progressive loss of brain function, liver failure

Question 12

Mitochondrial inheritence

Answer 12

• 100% maternal

- in fertilization, the ovum contributes all of the cytoplasm including organelles

Question 13

Heteroplasmy

Answer 13

• Mosaicism of mtDNA = variable amounts of WT and mutant chromosomes in each mitochondrion, cell, and tissue
• mtDNAs can have different sequences based on random mutation and each mitochondria has 2-10 DNA copies and each cell has 100s-1000s of mitochondria

Question 14

Heteroplasmy effect on cellular/organ phenotype

Answer 14

• cell containing mutant mtDNA may function normally
• if proportion of mutant mtDNA exceeds a certain threshold, cellular phenotype will be affected
• if a proportion of mutant cells reaches a threshold, organ phenotype will be affected

Question 15

Replicative segregation

Answer 15

• Progenitor cells may show heteroplasmy of mitochondria
• Oocyte production = bottleneck: at cell division, mitochondria are distributed unequally and do not necessarily reflect the ratio found in the progenitor cell

Question 16

Why are phenotypes associated with mitochondrial disorders highly variable? (variable penetrance and expressivity)

Answer 16

• Heteroplasmy within cells
• Proportion of cells with altered phenotype
• Sensitivity of tissue to impairment