Mitochondria Disease Flashcards
Give some mt functions
Produce atp from tca cycle and oxphos
Fe clusters as catalytic units eg in etc
Buffer ic calcium eg in muscles and neurones
What do they convert into atp
Fa and glucose
Where are the 5 multimeric protein complexes located
Inner membrane
What else other than the 5 complexes needed for atp gen
2 electron carriers ubiquinone and cytochrome c
Where are the electrons transferring down chain from
Reduced FAD and NADH (the h ions)
What does this allow
Protons to be pumped from matrix to intermembrane space and then down complex v (ATPase)
What does the mt dna look like
Circular
Intronless
13 peptides encoded
22 trna
2 RRNA (ribosomes)
Which complex has most genes encoded by mt
Complex 1
Which complex doesn’t have any subunits encoded by mt
II (succinate dehydrogenase)
Which complex 1 gene encodes by light strand (most genes are in heavy strand)
Mt-ND6
Why is it important trnas flank protein coding genes
Txn of the strands occurs all at once since no introns, so long messengers need to be processed and read correctly
What stops elongation of txn and is mutated in MELAS commonly
mTERF
Which non coding region does txn and replication of Mtdna start
D-loop
What is the promoter in d-loop for light strand txn
Light strand polycistron
H strand has 2 promoters. What is hsp1 for
Rrna encoding (ribosomes) and the first trna (leucine)
What does trna leu form
Clover lead
What is the other hsp for
Entire h strand txn
What txn activator needed by mt to bind to rna polymerase for txn activation
TFAM
How is mt inherited
Maternally, oocytes have 100,000 copies of mt dna
How can migration be tracked by mtdna
Overtime developed polymorphisms segregated through haplogroups
Each ethnic group can be indentfied by haplogroup segregation
What is the term for cells which only have wt mtdna xopies
Homoplasmic wt
What does heteroplasmy mean
Cells have a mix of mutant mtdna and wt xopies
What is the biochemical threshold
The threshold of exceeded by too high hereroplasmy %, the wt can’t compensate for the loss of activity by mutant copies = cell dysfunctionb
Which types of tissues likely have a lower threshold for hereroplasmy dysfunction
Those largely dependant on oxidative metabolism. Eg brain, retina, skeletal muscle
Which complex is used to compare other deficiencies eg cox/complex Iv deficiency
Complex II bc not mt encoded
Why would staining patterns show cells both blue and brown stained in a muscle
Cells blue might have less functional cox because higher hereroplasmy/mutation, others might have lower heteroplasmy so more cox functional
How can diff tissue types/ cells in a tissue have different heteroplasmy
Because of random segregation of mt during mitosis of cells in dividing tissues
What is a genetic bottleneck referring to in mtdna
PGCs segregate their mtdna copies so each oocyte only gets a few copies which are used to repopulate so oocyte has throuaands of copies
How does this process mean genetic inheritance of mt disease is hard to detect
Because segregation of mt dna xopies is random and depends on which oocyte is fertilised to then make the embryo deciding if more heteroplasmy or less
How many mt proteins does the nucleus encode
1100 around
What sorts of proteins are these
For nucleotide synthesis,for replication, for txn, translation, protein import, other oxphos subunits
What pattern of inheritance do nuclear genes follow
Mendelian (ie ar or ad)
What things for replication does nyckeus encode
Poly-gamma and twinkle helicase
Can nuclear gene mutations cause mt disease
Yes!! Eg polG , rrm2b
What does rrm2b do which is commonly mutated in mt diseases
Encodes a subunit of a ribonucleotide reductase which helps synthesise nucleotides for more mtdna synthesis
Why is replication of mtdna so important
Because mutational rate is so quick, it is essential to maintain functional dna
What is the term for the gradual increase/changes in heteroplasmy bc of unequal division or replication of mutant
Clonal expansion
How does it happen in non dividing/post mitotic tissues like neurones
The mtdna replicate /still being turned over bc of ros
Why do single large scale deletions allow faster replication
Smaller mtdna genome
What does this cause overtime
Increased cell heteroplasmy as faster mutant replication
Why would heteroplasmy never go beyond 90% or slowly heteroplasmy decreases
Would die
Selected against and die out overtime
What type of other mutation is there
Point mutation
What % of point mutations are inherited
75%, some are somatic
Even if 75% inherited, why is it hard to predict child
Mothers mutations may not have reached threshold
Explain the clinical heterogeneity of mt related syndromes
Different ages onset of symptoms and different severities due to different heteroplasmy levels
Which syndrome with 3 mutations is most common
Lhon
What is the most common point mutation
A>G3243
In mttl1 gene (trna leu)
What are the lhon mutations in
ND1,4 and 6 (complex 1)
What ndna mutations most common
Twinkle/PEO1, polG, rrbm2b
What is ptosis which is a neurological symptom
Droopy eyes
What is LHON
Bilateral vision loss due to retinal ganglion cells loss
What causes loss of rgcs
Increased ros and reduced oxphos
Does it have full penentrance
No
What % heteroplasmy needed for symptoms
76%
What haplotype were vision loss more likely
J
Why is it suggested a complex disease
Found nuclear gene snps increasing risk and also environment like smoking affect rgc survical
What is inefficient when mttl1 mutated
Translation
Why is complex 1 deficiency common in mttl1 mutant
Many genes encoded on the mtdna
What other syndromes seen in mttl1 mutant
Melas
Maternally inherited diabetes and deafness
Cpeo
Which syndrome associated with mttl1 needs a higher heteroplasmy to be seen
Melas (50-92%)
Single large scale deletions occur, what other deletion
Multiple deletions
How
Mutation in nuclear dna which affects mtdna maintenance/stability everytime it replicates
What are the 3 syndromes caused by the single large scale deletions
Pearsons,cpeo,kss
Why does kss have a later onset
Due to clonal expansion overtime occurring to reach threshold
What dominance pattern is multiple deletion syndromes
Ad or ar in the nuclear genes for maintenance eg twinkle, polg, rmtb2
How can you prevent mt disease passed into offspring
Prenatal screening
Egg donor
Preimplantation diagnosis (do ivf and look at heteroplasmy of embryo before implanted)
Mt donation
What 2 types of mt donation are there
Maternal spindle transfer
Pro nuclear transfer
