Mitochondrial myopathies Flashcards
Endosymbiotic theory
Theory that explains the origin of the mitochondria.
The mtDNA is theorised to be an evolutionary descendant of a prokaryote.
- Contains same sized ribosome (70s) and other similar features
Mitochondrion is thought to have developed an endosymbiotic relationship with an ancestral eukaryotic cell.
Mitochondrial DNA (mtDNA)
Circular double stranded DNA.
Mt genome is 16.5 Kb is size and there is 5-10 copies in each mitochondrion.
More than 900 different Mt proteins are encoded in nDNA and transported to the mt.
Differences between nDNA and mtDNA
- Size
- Number of DNA per cell
- Genes
- Introns
- Coding DNA
- Coding
- Associated proteins
- Mode of inheritance
Size: nDNA much larger.
Number of DNA molecules per cell:
nDNA= diploid, haploid
mtDNA= polyploidy
Genes: nDNA has way more genes
Introns: mtDNA contains no introns, nDNA does.
Coding DNA: Most of mtDNA is coding, whereas only around 3% of nDNA is coding.
Coding: mtDNA does not use the normal universal genetic code.
Associated proteins: mtDNA has no histones, whilst nDNA does.
Mode of inheritance: mtDNA is maternal, nDNA uses mendelian and paternal inheritance.
Maternal inheritance of mtDNA
During fertilsation, none of the sperm’s mitochondria is donated to the embryo
- All mitochondria is derived from the egg.
Mitochondrial genome
- What does it code for
13 of the genes codes for respiratory chain proteins.
2 codes for rRNA.
22 codes for tRNA- which differs from nuclear tRNA.
Mutation of mtDNA
- What causes it
- How does it differ from nDNA mutations
The respiratory chain is very close to mtDNA
- The chain produces ROS which damages mtDNA
mtDNA is less effective than nDNA in repairing DNA damage.
- mtDNA mutates x10 fold more rapidly than nDNA
With age, mtDNA accumulates.
Reduction of oxygen
O2–[4e-]–> H2O
- This occurs at the complex IV in the respiratory chain.
Oxygen can be partially reduced at other complexes to form ROS.
- O2–> O2-
- O2—> H2O2
- H2O2—> .OH + OH-
Reactive oxygen species
Chemically reactive species with oxygen.
- This is produced in the respiratory chain and can cause mtDNA damage.
Examples:
Superoxide anion: O2-
Hydroxyl anion: .OH
Periode ion O2(2-)
Hydrogen peroxide (H2O2)
Hypochlorous acid (HOCl)
Resolving ROS
There are antioxidant enzymes in the mitochondrion that convert ROS, into safer molecules.
H2O2:
Catalase
GPA
Prx3
Superoxide O2-:
MnSOD
Antioxidant that converts O2-
MnSOD
- manganese superoxide dismutase
Converts O2- into H2O2
Diseases that show OXPHOS enzymes strongly implicated [3]
Alzheimer’s
Parkinson’s
TII diabetes
Mitochondrial myopathies
Neuromuscular diseases that result from mt mutation
- Leads to decrease ATP production in a cell.
Especially affects cells that are less tolerable to low ATP:
- Neurones
- Myocytes
- Skeletal muscle cells
- Pancreatic beta-cells
Symptoms of Mt myopathies
Begins with exercise intolerance/ muscle weakness
Heart failure/ arrhythmias
Dementia
Deafness
Blindness
Seizures
Clinical presentation of mt myopathies
Presentation is very variable due to heteroplasmy [threshold effect] and genetic bottleneck.
Threshold effect
This describes the proportional of defective mtDNA in a cell required to cause disease in a person.
- usually 70%
The proportion is unpredictable due to the nature of cell division:
Mitochondria are unequally divided during cell division so a cell can be heteroplasmic or homoplasmic.
Mt genetic bottleneck
In primordial germ cells, there can be mutant mtDNA which are randomly selected in cell division to form a primary oocyte.
The primary oocyte have their mitochondria multiply and the population of mt is different from the original primordial germ cell.
This can either cause a very high or low level of mutation in the cell before fertilisation.
Biochemical classification of Mt myopathies
Defects in mitochondrial transport systems.
Defects of substrate utilisation.
Defects of TCA cycle.
Defects of OXPHOS coupling.
Defects in oxidative phosphorylation
LHON syndrome
Leber’s hereditary optic neuropathy.
A Mt myopathy caused by Single base pair chain in ND4 gene.
- Affects Complex I
Defective e- transport from NADH to Ubiquinone
OR A single base change in the mt gene for cyt b. - Affects complex III
Results:
Optic nerve damage= blindness
Why can those with the LHON syndrome still survive despite a OXPHOS mutation?
The mutation affects either complex I, thus electron transport between NADH and UQ.
Electrons can still reach UQ via succinate, through succinate dehydrogenase.
This can support some metabolism in cells that are not very active.
But it cannot support the active metabolism of neurones
MERRF syndrome
Myoclonus epilepsy with ragged-red fibre.
Mitochondrial myopathy caused by a point mutation in the gene for lysine tRNA.
Affects:
Protein synthesis for oxidative phosphorylation.
Characterised by abnormally shaped mitochondria seen as ‘ragged-red fibres’ in staining..
Most common mutation in MERRF syndrome
Point mutation at position 8344 in the mt genome.
Ragged red fibres
Clumps of defective mitochondria that appear red after staining with Gomori modified Trichrome.
These clumps accumulate in aerobic skeletal muscle fibres.
MELAS syndrome
Mitochondrial encephalomyopathy
Mt mutation in genes:
ND5 (complex I)
TH, TL1, TV (tRNA)
Symptoms: Lactic acidosis Stroke like episodes Seizures w/ loss of vision Myoclonus Dementia
KSS
Kerns-Sayre syndrome
Mutation: 5kb deletion of mt genome
Onset: occurs before age 20.
Symptoms/ presentation:
Short stature
Endocrinopathies
Dementia Retinitis pigmentosa Lactic acidosis Heart conduction defects Raised protein content in CSF
Treatments for mitochondrial myopathies
Occupation/ physical therapy:
- Extend range of muscle movement
Vitamin therapies:
Riboflavin, creatine, CoQ etc to improve function (co enzymes)
Possible mt genome manipulation
Treatment’s effectiveness depends on patient’s metabolism.
Prevention of mitochondrial myopathies.
IVF strategy: used to replace defective mitochondrial inherited from mother
- Pro-nuclear stage mitochondrial gene replacement
- Maternal spindle transfer
Pro-nuclear mitochondrial gene replacement
Method used in IVF to replace defected mitochondria inherited from mother.
- Following eggs are fertilised with chosen father’s sperm:
- Mother’s egg with abnormal mitochondria.
- Donor’s egg with normal mitochondria. - Both eggs form a zygote. Donor’s zygote is taken from it egg and replaced with patient’s zygote.
- Zygote not grows in egg with normal mitochondria with selected maternal and paternal nuclear genome.
- Cleaving embryo is now transferred into the uterus of the chosen mother.
Maternal spindle transfer
Method used in IVF to replaced defective mitochondria inherited from mother.
- Both patient and donor’s eggs are unfertilised.
- Karyoplast from patient’s egg that contain spindle and associated chromosomes is fused into enucleated donor’s egg.
- Karyoplast from donor’s egg is removed and discarded. - Reconstituted egg is fertilised with spermout from patient’s father.
- Cleaving embryo with normal mitochondria and maternal and paternal genome is transferred into uterus.
