Mitochondria Genetics

Question 1

Describe general anatomy of mt genome

Answer 1

DNA are H(G rich) or L(C rich). Only noncoding = displacement loop = control region = Ori of rep for H, promotes transC of H and L. H is all coding except D loop.
L= 1 mRNA, svrl tRNA, 2 rRNA prox, tRNA displaced flanking most genes
13 proteins produced = Ox-phos prots
mt genome = 2 rRNA, 22 tRNA, 13 prot

Question 2

Describe the general replication of mtDNA

Answer 2

Ori rep of H (Oh) diff than OL, 2-10 mtDNA genomes per organelle so cell has k’s of mt genomes. Rep of mtDNA independent of nuclear DNA rep

Question 3

Describe mtDNA poly

Answer 3

DNA poly gamma only poly in mt, mut in PolG = disorders associated with decreased levels of mtDNA and/or multi mutations in mtDNA (large deletions)

Question 4

Describe progressive external optholmoplegia (PEO)

Answer 4

18-40 yrs, bilat ptosis, weak ext eye M, prox M wasting, exercise intolerance
mtDNA depletion or multi large deletions
AD, mut PolG but also muts in twinkle (mt Helicase)

Question 5

Describe Acquired mt myopathy HIV w/ reverse transcriptase inhibitors

Answer 5

AZT phosphorylated leads to triphosphate derivative which competes with dTTP for incorporation into DNA by reverse transC therefore AZT terms rev transC
DNA polG doesn’t accept tri deriv but is inhibited by AZT leading to myopathy

Question 6

Describe mt TransC

Answer 6

Promoters in central region (HSP and LSP) for both strands which also transC at same rate
Both processed by RNA endonucleases to sep tRNA, rRNA, and poly-adenylated mRNA
Secondary structure adopted by RNA regions coding for tRNA are recog pts for RNA endonuclease

Question 7

Describe protein synthesis in mt

Answer 7

Resemble bacterial (transL with methianine), relaxed codon usage (22 tRNAs vs 30), variant and code for respiratory chain

Question 8

What are the codon variations in mt

Answer 8

(codon, universal, mt) (UGA, stop, Trp) (AUA, Ile, Met) (AGA + AGG, Arg, Stop)

Question 9

Describe mtDNA variability

Answer 9

mainly SNPs, small deletions and insertions.

Due to ORI polymorphic and accumulation occurs 10x faster (ROS activity)

Question 10

What is mt mode of inheritence

Answer 10

Vert pedigree, maternal, mothers children all infected but variable

Question 11

What are the mutations associated with mtDNA

Answer 11

1. Rearrangement, gen deletions or duplications in mtDNA
2. Pt mutations in tRNA impairing mt prot synth
3. Missense mutations in coding region of genes altering Ox-phos action
   Most mtDNA mutations affect via direct or indirect Ox-phos and ATP prod
   Lactic acidosis = common finding along with ragged red M fibers

Question 12

What is Heteroplasmy

Answer 12

Heterplasm = normal, many diseases show a positive correlation with proportion of mutated mtDNA molecules inherited from mother. (mutations hetero, homo = dead)

Question 13

Describe giant deletions

Answer 13

Del up to 7kbp, heteroplasmic, sporadic, detected via S blot and PCR

Question 14

What are the diseases associated with giant deletions

Answer 14

1. D1: PEO, pheno = autosomal
2. D2: Kearns Sayre Syn (KSS) - without bone marrow involvment, late onset, mtDNA del in M, ragged fibers, prog ext opthalomegaly, retinopathy, cerebellar ataxia, heart block
3. D3: Pearson Syn - with bone marrow involvement, pediatric, pinocytopenia, sidroblast anemia, exocrine pancreatic failure

Question 15

What the mutations associated with mt-tRNA

Answer 15

MELAS - short, stroke-like, diabetes, tRNA(Lys) mut hetero

MERRF - progressive myocleric epilepsy and seizures. tRNA(lys) mut

Question 16

What are the mutations in protein coding genes

Answer 16

1. LHON - subacute bilat vision fail, X-chrom, decreased penetrance, onset around 24 yrs. Missense mutation in complex 1 subunit may be homo
2. NARP - Neurogenic muscle weakness, ataxia, retinitis pigmentosa, late child onset. ATPase 6 gene mutation