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24 Cards in this Set
- Front
- Back
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MT DNA:
general features patterns and peculiarities of inheritance types of mutations collaboration to Nuclear DNA mito disorders functional siginificance of mito |
overview
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main function of mito
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Ox Phos
metabolite syn: heme, sterols, aa Ca homeostasis sensor of death sig |
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Mito role in apop
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stimuli (ca?) causes formation of pores and release of cyto c (activates caspases which dismantle the protein cellular network), AIF(apop inducing factor), endonuclease G, Smac aka DIABLO (proapoptotic protein)
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mito DNA
copies of DNA inheritance number of genes control/regulation non-coding region |
circular
polyplasmy - 2-10 copies in each mito maternal inheritance 37 genes (13 respiratory chain, 2 RNA's and 22 tRNA) transcription and regulation controlled by nuclear proteins D loop only non-coding region;origin of dna rep |
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mtDNA vs Nuclear DNA
introns and exons intergenic space codons UAA insertion mutation rate repair mech |
no introns
coding sequences are contiguos or sep'd by only 1-2 bp codon usage difference start stop R W and I codons diff insertion of UAA at the TRANSCRIPTIONAL level mutation rate 10 to 100X more dna repair is lacking |
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how can you distinguish mito inheritance vs x-linked?
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males cannot transmit the defect
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ratio of defective/normal mtDNA
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in ova, will affect inheritance, severity and onset
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heteroplasmy
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mixture of normal and mutated DNA
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heteroplasmy and threshold
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mutant mtDNA's must be above a certain threshold to produce clinical manifestations
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heteroplasmy
what causes variation in percent mutant mtDNA needed to cause cell dysfunction? |
tissue ox phos requirements
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what tissues do mito diseases hit heaviest
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heart brain muscle
anything with high enerygy consumption |
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mitotic segregation
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mutant mtDNA can segregate unequally upon mitosis and cause crossing of threshold
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skewed heteroplasmy
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threshold surpassed in 1 tissue
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how many nuclear proteins need to be importend from the cytosol to a mito
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at least 1000
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mito targeting signals
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recognized by TIM and TOM, n-terminal sequence and amphipathic alpha helix/ chaperone proteins
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when to suspect mitochondrial dysfunction
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when a common diseasea has atypical features
three or more organs involved setbacks or flare ups in chronic disease occurs w/infections |
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LHON
stands for symptoms mutation |
leber hereditary optic neuropathy
midlife central vision loss variable penetrance heteroplasmy may determine severity ND6 mutation, ala to val in NADH dehydrogenase low percentage mtDNA mutant = LHONS higher = LDTY |
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Protein synthesis mutations
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rRNA of tRNA mutations
base substitutions |
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two diseases caused by tRNA mutations
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MELAS(mito encephalomyopathy, lactic acidosis, and stroke-like episodes) and MERRF(myoclonic epiliepsy and ragged red fiber)
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two deletion and rearrangement diseases
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CPEO[chronic progressive external opthalmoplegia, shows decreased COX stain] and KSS [kearns-sayre syndrome](5kb deletion)
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somatic mutations
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oxphos activity declines with age in brain muscles liver
increase in COXnegative fibers |
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how many hits/cell/day of redox damage
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10,000 hits per cell a day
so 7X10^12 hits/sec |
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AZT therapy and mitochondria
muscle signs high levels of serum_____ |
70-80% depletion
myopathy with increased drug dose muscle signs: proximal weakness, myalgia, wasting high serum creatine improvement with cessation after 3-4 months |
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myopathology associated with AZT
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necrosis
mito prolif: succinate deH and fibers fiber size variability inflammation |
