mitochondrial myopathies Flashcards
what is mitochondrial DNA like
Closed circular double stranded molecule
Human mt genome 16.5 kb
5-10 copies of genome in each mitochondrion (a cell has 2-2000 mitochondria)
>900 different mt proteins encoded by nDNA, translated on cytosolic ribosomes, important and then assembled in mt
what are the origins of mitochondria
Endosymbiotic origin Many features (circular DNA/70S ribosomes) of mt genetic system resemble prokaryotes Strengthened theory mt are evolutionary descendants of prokaryote Result of endosymbiotic relationship with ancestral eukaryotic cells early in history of life on earth
how are mitochondria inherited
embryo derives all mt from egg, most sperm mt in tail so not absorbed or destroyed if they do enter
maternally
what is the mitochondrial genome
Many of the genes needed for mt function have moved from mt into nuclear genome
Mt genome codes for
13 of resp chain proteins, 2 rRNA, 22 tRNA
Another difference – tRNA structures different from nuclear tRNA
how are mitochondria effected by 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 implicated in Alz/Park and T2D
Defects in OXPHOS – involves tissues most reliant on it, occurs later in life, progressive with age, progressive enrichment in mutated mtDNAs
what is REDOX used for
REDOX reactions essential for cell metabolism
OIL RIG important for e- carriers NAD+, NADP+, FAD+
Reduction of oxygen O2 +4e->H20
O2 O2- H2O2 OH and OH- H2O (add 1 e-)
what are reactive oxygen species (ROS)
Superoxide anion O2- Hydroxyl radical HO Peroxide ion O2 2- Hydrogen peroxide H2O2 Hypochlorous acid (HOCl)
How are ROS generated in the mitochondria
by complexes I, III and IV
how is the efficiency of OXPHOS affected by ageing
ETC is major producer of ROS
Mt genome suffers greatest exposure to and damage by ROS
Mt DNA less effective at correcting mistakes and damage of DNA
how do mitochondrial diseases occur
Arise from defects in mt enzymes and systems eg TCA cycle and OXPHOS rare
Major defects incompatible with life and affected embryos rarely survive
Over 150 different diseases, some linked to mtDNA
Often involve CNS and musculoskeletal system (aka mt myopathies)
how are mitochondrial diseases classified biochemically
1 defects of mt transport systems (carnitine palmitoyltransferase CPTI and II) deficiencies
2 defects of substrate utlisation (pyruvate dehydrogenase complex (PDC) deficiency and fatty acid oxidation defects)
3 defects of TCA cycle (fumarase deficiency or a0ketoglutarate dehydrogenase deficiency)
4 defects of OXPHOS coupling (Luft’s syndrome)
5 defects of oxidative phosphorylation (complex I/II/III/IV/V deficiencies – defects of ETC components)
what are mitochondrial myopathies
A number of human diseases are attributed to mutations in mt genes in mtDNA that reduce capacity of cells to produce ATP
Group of neuromuscular diseases, most occur before 20, often as exercise intolerance or muscle weakness, other symptoms include HF, heart rhythm disturbances, dementia, deafness, blindness and seizures
how are cells affected by mitochondrial myopathies
Some tissues eg neurons, myocytes, skeletal muscle cells and B cells of pancreas are less able to tolerate lowered ATP production
how is inheritance of mitochondrial diseases determined
Onset of clinical symptoms, phenotypic variability and variable penetrance of mt disease governed by
Homoplasmy and heteroplasmy of mt – threshold effect
Genetic bottleneck
what is the threshold effect
progenitor cell with heterogeneous mt divide, distribute mt unevenly
varying amount of mutant mt, certain percentage will meet threshold and classify as disease
