White Lecture 8: "Mitochondrial Genetics and Disease"

Question 1

Which parent does mitochondrial inheritance come from?

Answer 1

Maternal

Question 2

What are the mitochondrial diseases?

Answer 2

1. MELAS
2. MERFF
3. Chronic progressive external ophthalmoplegia
4. Kearns-Sayre syndrome
5. LHON

Question 3

What is the function of mitochondria and what are the two ways that it achieves this?

Answer 3

Provide cellular energy in the form of ATP in the cell

ETC: pump H+ ions to the space between the membranes oxidative phosphorylation

Question 4

Describe mitochondrial DNA

Answer 4

have their own genome
contains 37 genes for 13 proteins and 24 parts of the machinery to make proteins
replicates

Question 5

Define mitochondrial myopathy

Answer 5

muscle disease caused by mitochondrial dysfunction

Question 6

Define MERRF

Answer 6

myoclonus epilepsy with ragged red fibers

Question 7

Define MELAS

Answer 7

mitochondrial encephalopathy lactic acidosis and stroke-like episodes

Question 8

Define KSS

Answer 8

Kearns-Sayre Syndrome

Question 9

Define CPEO

Answer 9

Chronic Progressive external ophthalmoplegia

Question 10

Define LOH

Answer 10

Leber Hereditary Optic Neuropathy

Question 11

What are the clinical characteristics of mitochondrial myopathies?

Answer 11

muscle weakness
exercise intolerance 
lactic acidosis 
neurological signs 
other abnormalities

Question 12

Define mitochondrial myopathy

Answer 12

degeneration of muscle fibers caused by accumulation of abnormal mitochondria

Question 13

Define ragged red fibers

Answer 13

aggregates of abnormal mitochondria from red sarcolemmal blotches

Question 14

Define heteroplasmy

Answer 14

a mixture of normal mitochondria and mutant mitochondria occurs in one cell

Question 15

Define threshold

Answer 15

if cells carry too many mutant mitochondria, disease results

Question 16

Which tissues are most effected by mitochondrial diseases?

Answer 16

Neurological and muscular

Question 17

Describe the Mitochondrial respiratory chain

Answer 17

• 87 proteins

- encoded by nuclear and mitochondrial genome

Question 18

Describe the 5 complexes for mitochondrial respiration

Answer 18

ETC has 4 enzyme complexes: I to IV oxidize NADH and FADH2
Complex V is an ATP synthetase uses the H+ ion gradient to alter ADP and ATP

Complexes I through V are encoded by nuclear DNA and mtDNA

Question 19

Describe each of the complexes in terms of how many subunits they have.

Answer 19

Complex I  - 7 subunits 
Complex II- none 
Complex III- 1 subunit 
Complex IV- 3 subunits 
Complex V- 2 subunits

Question 20

Where does the transcription and translation of the mt mRNA occur?

Answer 20

In the mitochondria

Question 21

Describe mtDNA

Answer 21

16569 base pairs 
no DNA repair mechanism 
no recombination of the mitoDNA 
10X higher mutation rate than nuclear DNA 
inherited from the mother

Question 22

What do point mutations in mtDNA tRNA lead to?

Answer 22

MELAS and MERRF

Question 23

What do mtDNA genome deletions and rearrangements lead to?

Answer 23

KSS and CPEO

Question 24

Describe MERRF

Answer 24

Myoclonus Epilepsy with Ragged Red Fibers
myoclonus- often the first symptom (involuntary jerking)
ataxia
ragged red fibers (muscle tissue)
seizures and dementia

due to heteroplasmy

90% caused by 2 mutations of tRNA Lys

85% of MERRF cases due to A to G mutations in the mtDNA tRNA-lys gene at the nucleotide position 8344
5% of MERRF cases: G to C at the position 8356 in tRNA-lys mtDNA gene

genotype/phenotype correlation

Question 25

Describe MELAS

Answer 25

Mitochondrial Encephalopathy Lactic Acidosis with Stoke-like episodes

Clinical presentation: seizures, blindness, headaches, anorexia, recurrent vomiting, lactic acidosis, ragged red fibers

age of onset 2-10

caused by A3243G mutation in t-RNA-leu

Question 26

Describe Kearns-Sayre-Syndrome

Answer 26

• onset before age 20
• retinitis pigmentosa (degenerative eye disease)
• at least one of the following: cardiac conduction abnormality, cerebellar ataxia, cerebral spinal protein

mitochondrial mutations: 85% of KSS is due to mtDNa rearrangements including duplicated mtDNA, deleted mtDNA and insertions

200 different deletions

Red Ragged fibers in skeletal muscle

Question 27

Describe CPEO

Answer 27

Chronic Progressive External Ophthalmoplegia

mild to moderate mitochondrial myopathy - mtDNA rearrangements

Ptosis- drooping of the eyelid

Question 28

Describe LHON

Answer 28

Leber Hereditary Optic Neuropathy
“honorable mention”

mitochondrial mutation only affects optic nerve

no muscle involvement; central vision loss, degeneration of the retinal ganglion cell layer and optic nerve

-onset and progression is rapid: initially effects one eye but both eyes can be affected at the same time

mutations affect mtDNA genes encoding complex 1 proteins