Mitochondrial Myopathies Flashcards
Mitochondrial DNA
Closed, circular, double stranded molecule
Human mt genome is 16.5kb
5-10 copies in each mitochondrion (each cell has 2-200 mitochondria)
>900 different mt proteins are encoded by nDNA, translated on cytosolic ribosomes, imported and then assembled in the mitochondrion
Origins: endosymbiotic relationship with ancestral eukaryotic cells early on - mirochondria are evolutionary descendants of prokaryotes
Introns are absent
1 gene per 450 base pairs (more dense than nDNA)
Maternal Inheritance
The embryo essentially derives all its mitochondria from the egg
Most sperm mitochondria are in the tail (not absorbed on fertilisation)
Any paternal mitochondria that enter the egg are destroyed
Mitochondrial Genome
Many of the genes needed for mitochondrial function have moved into the nuclear genome over time
Mt genome codes for
13 of the respiratory chain proteins (7 subunits of Complex 1, 1 of CIII, 3 of CIV, 2 subunits of ATP synthase)
2 rRNA
22 tRNA
Another difference is tRNA structure differs from nuclear tRNA
Mitochondria and Ageing
Efficiency declines with age
Partly as a result of accumulation of damage and mutations to mtDNA caused by ROS
Defects in OXPHOS are strongly linked to Alzheimer’s, Parkinson’s and T2 diabetes
Defects in OXPHOS: involve tissues most reliant on OXPHOS, occurs later in life, progressive with age, show progressive enrichment in mutated mtDNAs
Examples of ROS: superoxide anion (O2-), hydroxyl radical (HO), peroxide ion (O22-), H2O2, hypochlorous acid (HOCl)
Efficiency of OXPHOS with ageing
Respiratory chain is the major producer of ROS
mt genome suffers the greatest exposure to and damage by ROS
mt DNA less effective at correcting mistakes and repairing mt DNA damage
Mitochondrial Diseases - biochemical classification
Defects of mitochondrial transport systems: carnitine palmitoyltransferase (CPT I & II) deficiencies
Defects of substrate utilisation: pyruvate dehydrogenase complex deficiency, fatty acid oxidation defects
Defects of TCA cycle: fumarase deficiency or alpha ketaglutarate dehydrogenase deficiency
Defects of OXPHOS coupling: Luft’s syndrome
Defects of OXPHOS: complex I/II/III/IV deficiencies (defects of resp chain components)
Mitochondrial myopathies
A number of human diseases are attributed to mutations in mt genes in mtDNA that reduce the capacity of cells to produce ATP
Some tissues/cell types e.g. neurons, myocytes, skeletal muscle cells and the -cells of the pancreas are less able to tolerate lowered ATP production
Group of neuromuscular diseases which present before age 20, beginning with exercise intolerance or muscle weakness
Other symptoms include HF, rhythm disturbances, dementia, deafness, blindness, seizures
Heterogeneity of mitochondrial disease
Onset of clinical symptoms, phenotypic variability and variable penetrance are governed by
Homoplasmy and heteroplasmy of mt -> threshold effect
Mt genetic bottleneck
LHON syndrome - Lebers hereditary optic neuropathy
Single base change in the mt gene ND4, (from Arg to His) in a polypeptide of Complex I
Mitochondria partially defective in e- transport from NADH to ubiquinone
Some ATP produced by e- transport from succinate, but not enough to support the very active metabolism of neurons
Results in damage to the optic nerve and leads to blindness
A single base change in the mt gene for cyt b in complex III also produces LHON
MERRF Syndrome - myoclonus epilepsy with ragged red fibre
Caused by a point mutation in the mt gene encoding a tRNA specific for lysine (tRNALys)
Disrupts synthesis of proteins essential for oxidative phosphorylation (ATP synthesis)
MERRF syndrome is caused by a mutation at position 8344 in the mt genome in over 80% of cases
Many other genes are involved and include: mt – TK, mt - TL1, mt – TH, mt – TF
Skeletal muscle fibres of MERRF patients have abnormally shaped mitochondria
Ragged red fibres:
- Clumps of defective mitochondria accumulate in aerobic skeletal muscle fibres (appear red after staining with Gomori modified Trichrome)
- Associated with mitochondrial disease
MELAS syndrome - mitochondrial encephalomyopathy
Mt myopathy affecting primarily the brain and skeletal muscle - mt gene dysfunction involving mt ND5 (complex I) and mt-TH, mt-TL1 and mt-TV (all involved with tRNA)
Symptoms appear in childhood and include: build-up of lactic acid (lactic acidosis), stroke-like episodes with muscle weakness, seizures leading to loss of vision, movement difficulties (incl. involuntary muscle spasms (myoclonus) and dementia
KSS - Kearns-Sayre Syndrome
Results from a 5kb deletion of the mt genome
Onset before age 20
Affected patients have short stature and often have multiple endocrinopathies including diabetes
Symptoms include dementia & retinitis pigmentosa
Other symptoms include lactic acidosis, heart conduction defects and raised cerebrospinal fluid protein content
Treatment of mitochondrial myopathies
Diagnosis: combination of biochemical tests, histology & genetic testing
Prognosis: variable and dependent on the type of disease and the patient’s metabolism (varies greatly between individuals)
Occupational / physical therapy may extend the range of muscle movement. Vitamin therapies such as riboflavin, creatine, CoQ, C, K and carnitine may improve function for some
No specific treatments. Development of genetic strategies for manipulating the mt genome
Prevention of mitochondrial myopathies
IVF strategy designed to replace defective mitochondria inherited from a mother
Malfunctioning mitochondria are replaced by the donor healthy ones
Strategy involves merging DNA from two eggs - one from the mother with defective mitochondria, the other from a healthy donor with functioning mitochondria
Approved by UK parliament in February 2015
First licence approved in March 2017
Mitochondrial gene replacement (pronuclear stage)
Maternal spindle transfer (alternative strategy)
