Mitochondria Disease Flashcards by Anna Safrankova

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

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What do they convert into atp

Fa and glucose

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Where are the 5 multimeric protein complexes located

Inner membrane

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What else other than the 5 complexes needed for atp gen

2 electron carriers ubiquinone and cytochrome c

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Where are the electrons transferring down chain from

Reduced FAD and NADH (the h ions)

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What does this allow

Protons to be pumped from matrix to intermembrane space and then down complex v (ATPase)

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What does the mt dna look like

Circular
Intronless
13 peptides encoded
22 trna
2 RRNA (ribosomes)

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Which complex has most genes encoded by mt

Complex 1

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Which complex doesn’t have any subunits encoded by mt

II (succinate dehydrogenase)

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Which complex 1 gene encodes by light strand (most genes are in heavy strand)

Mt-ND6

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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

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What stops elongation of txn and is mutated in MELAS commonly

mTERF

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Which non coding region does txn and replication of Mtdna start

D-loop

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What is the promoter in d-loop for light strand txn

Light strand polycistron

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H strand has 2 promoters. What is hsp1 for

Rrna encoding (ribosomes) and the first trna (leucine)

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What does trna leu form

Clover lead

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What is the other hsp for

Entire h strand txn

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What txn activator needed by mt to bind to rna polymerase for txn activation

TFAM

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How is mt inherited

Maternally, oocytes have 100,000 copies of mt dna

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How can migration be tracked by mtdna

Overtime developed polymorphisms segregated through haplogroups

Each ethnic group can be indentfied by haplogroup segregation

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What is the term for cells which only have wt mtdna xopies

Homoplasmic wt

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What does heteroplasmy mean

Cells have a mix of mutant mtdna and wt xopies

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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

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Which types of tissues likely have a lower threshold for hereroplasmy dysfunction

Those largely dependant on oxidative metabolism. Eg brain, retina, skeletal muscle

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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

What % heteroplasmy needed for symptoms

76%

What haplotype were vision loss more likely

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