mitochondrial myopathies Flashcards
what are the key characteristics of mitochondrial DNA?
- closed circular double stranded molecule
- human mt genome is 16.5kb
- 5-10 copies of the genome in each mitochondrion
- > 900 different mt protein are enclosed by the nDNA translated of cytosolic ribosomes, imported then assembled in the mitochondrion
what is the endosymbolic origin of mitochondria?
- many features of the mt genetic system resemble those found in prokaryotes
- strengthened the theory that mitochondria are the evolutionary descendants of a prokaryote
- result of an endosymbiotic relationship with ancestral eukaryotic cells early in the history of life on earth
what is present in the mitochondrial genome?
- many of the genes needed for mitochondrial function have moved from the mitochondrion into the nuclear genome over evolutionary time
- mt genome codes for: 13 of respiratory chain proteins, 2 rRNA, 22 tRNA
- another difference: tRNA structure differs from nuclear tRNA
how does mitochondria link to ageing?
- efficiency declines with age
- partly as a result of the accumulation of damage and mutations to mtDNA caused by ROS
- defects in oxidative phosphorylation are strongly implicated in Alzheimer’s/Parkinson’s and type II diabetes
- defects in oxidative phosphorylation (OXPHOS): involve tissues most reliant on OXPHOS, occurs later in life, progressive with age, show progressive enrichment in mutated mtDNAs
how does efficiency of OXPHOS link with ageing?
- respiratory chain is the major producer of reactive oxygen species (ROS)
- mt genome suffers the greatest exposure to, and damage by, ROS
- mt DNA less effective at correcting mistakes and repairing mt DNA damage
what are the general characteristics of mitochondrial diseases?
- diseases arising from defects in mt enzymes and systems are rare
- major effects are incompatible with life and affected embryos very rarely survive
- however there are over 150 different mitochondrial disease and some are linked to mtDNA
- often involve CNS and musculoskeletal system
what are the biochemical classifications of mitochondrial diseases?
1) defects of mitochondrial transport systems: carnitine palmitoyltransferase deficiencies
2) defects of substrate utilisation: pyruvate dehydrogenase complex deficiency, fatty acid oxidation defects
3) defects of TCA cycle: fumarase deficiency or alpha-ketoglutarate dehydrogenase deficiency
4) defects of OXPHOS coupling: Luft’s syndrome
5) defects oxidative phosphorylation: complex I/II/III/IV deficiencies
what are mitochondrial myopathies?
- a number of human diseases are attributed to mutations in mt genes in mtDA that reduce the capacity of cells to produce ATP
- some tissues/cell types are less able to tolerate lowered ATP production
- group of neuromuscular diseases
- most occur before the age of 20, often beginning with exercise intolerance or muscle weakness
- other symptoms include heart failure/rhythm disturbances, dementia, deafness, blindness and seizures
what are the heterogeneity of mitochondrial diseases?
onset of clinical symptoms, phenotypic variably, and variable penetrance of mt diseases are governed by:
- homoplasmy and heteroplasty of mt —> threshold effect
- mt genetic bottleneck
what are the 4 main mt myopathies caused by mutations in mtDNA?
- LHON: lebers hereditary optic neuropathy
- MERRF: myoclonus epilepsy with ragged-red fibre
- MELAS: mitochondrial encephalomyopathy
- KSS: Kearns-sayre syndrome
what are the key characteristics of LHON?
- single base chain in the mt gene in complex I
- mitochondria partially defective in electron transport from NADH to ubiquinone
- some ATP produced by electron 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 in complex III also produces LHON
what are the key characteristics of MERRF syndrome?
- caused by point mutation in the mt gene encoding a tRNA specific for lysine
- disrupts synthesis of proteins essential for oxidative phosphorylation (ATP synthesis)
- skeletal muscle fibres of MERRF patients have abnormally shaped mitochondria
- clumps of defective mitochondria accumulate in aerobic skeletal muscle fibres
what are the key characteristics of MELAS syndrome?
- mt myopathy affecting primarily the brain and skeletal muscle
- mt dysfunction
- symptoms appear in childhood and include: buildup of lactic acid, stroke like episodes with muscle weakness, seizures leading to loss of vision, movement difficulties and dementia
what are the key characteristics of KSS?
- results from a deletion of the mt genome
- onset before age 20
- affected patients have short stature and often have multiple endocrinopathies including diabetes
- symptoms include: dementia and retinitis pigmentosa
- other symptoms include: lactic acidosis, heart conduction defects and raised cerebrospinal fluid protein content
what is the treatment for mitochondrial myopathies?
- diagnosis: combination of biochemical tests, histology and genetic testing
- prognosis: variable and dependent on the type of disease and the patients metabolism
- occupational/physical therapy: may extend range of muscle movement
- vitamin therapies: riboflavin, creation, CoQ, C, K and carotene may improve function for some
- no specific treatments: development of genetic strategies for manipulating the mt genome
