White Lecture 8: "Mitochondrial Genetics and Disease" Flashcards
Which parent does mitochondrial inheritance come from?
Maternal
What are the mitochondrial diseases?
- MELAS
- MERFF
- Chronic progressive external ophthalmoplegia
- Kearns-Sayre syndrome
- LHON
What is the function of mitochondria and what are the two ways that it achieves this?
Provide cellular energy in the form of ATP in the cell
ETC: pump H+ ions to the space between the membranes oxidative phosphorylation
Describe mitochondrial DNA
have their own genome
contains 37 genes for 13 proteins and 24 parts of the machinery to make proteins
replicates
Define mitochondrial myopathy
muscle disease caused by mitochondrial dysfunction
Define MERRF
myoclonus epilepsy with ragged red fibers
Define MELAS
mitochondrial encephalopathy lactic acidosis and stroke-like episodes
Define KSS
Kearns-Sayre Syndrome
Define CPEO
Chronic Progressive external ophthalmoplegia
Define LOH
Leber Hereditary Optic Neuropathy
What are the clinical characteristics of mitochondrial myopathies?
muscle weakness exercise intolerance lactic acidosis neurological signs other abnormalities
Define mitochondrial myopathy
degeneration of muscle fibers caused by accumulation of abnormal mitochondria
Define ragged red fibers
aggregates of abnormal mitochondria from red sarcolemmal blotches
Define heteroplasmy
a mixture of normal mitochondria and mutant mitochondria occurs in one cell
Define threshold
if cells carry too many mutant mitochondria, disease results
Which tissues are most effected by mitochondrial diseases?
Neurological and muscular
Describe the Mitochondrial respiratory chain
- 87 proteins
- encoded by nuclear and mitochondrial genome
Describe the 5 complexes for mitochondrial respiration
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
Describe each of the complexes in terms of how many subunits they have.
Complex I - 7 subunits Complex II- none Complex III- 1 subunit Complex IV- 3 subunits Complex V- 2 subunits
Where does the transcription and translation of the mt mRNA occur?
In the mitochondria
Describe mtDNA
16569 base pairs no DNA repair mechanism no recombination of the mitoDNA 10X higher mutation rate than nuclear DNA inherited from the mother
What do point mutations in mtDNA tRNA lead to?
MELAS and MERRF
What do mtDNA genome deletions and rearrangements lead to?
KSS and CPEO
Describe MERRF
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
Describe MELAS
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
Describe Kearns-Sayre-Syndrome
- 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
Describe CPEO
Chronic Progressive External Ophthalmoplegia
mild to moderate mitochondrial myopathy - mtDNA rearrangements
Ptosis- drooping of the eyelid
Describe LHON
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
