Hot topic - Mitochondrial Flashcards
How large is the mtgenome, how many genes does it code for and how many protein coding genes?
16.6kb
37
13: all proteins involved in OxPhos. Remainder are 2 rRNAs and 22 tRNAs.
What is unusual about mitochondrial termination codons?
They are added post-transriptionally
Why does mtDNA have a higher mutation rate(10x) than nuclear DNA?
It is located closer to the sites of reactive oxygen species generation, so more oxidative damage occurs.
What three classes of disease are related to mitochondrial dysfunction?
Primary mt disease
Neurodegeneration
Cancer
What is the carrier rate for mitochondrial disease?
1/200
What is the required clinical threshold for deleted mtDNA molcules
50-60%
What is the required clinical threshold for point mutation in tRNA genes?
> 90%
Which organ systems are frequently affected? Why?
Renal tubules Skeletal muscle Cardiac muscle Neurons Cochlear hair cells
They are highly post-mitotically active and have high energy demands
What is the difference in age at presentation between mtDNA mutations and nDNA mutations?
mtDNA mutations tend to appear in childhood; nDNA mutations in adulthood.
Name the common mtDNA disorders. State whether they show disease in heteroplasmic or homoplasmic forms, and name their common mutation.
Deletion disorders:
KSS - Several deleted genes, heteroplasmic
CPOE - Several deleted genes, heteroplasmic
Pearson - Several deleted genes, heteroplasmic
Point mutation disorders: LHON - MT-ND1 (m.3460G>A), ND4 (m.11778G>A), ND6 (c.14484T>C), hetero and homoplasmic MELAS - MT-TL1 (m.3243A>G) Heteroplasmic MERFF - MT-TK (m.8344A>G) Heteroplasmic MIDD - MT-TL1 (m.3243A>G), Heteroplasmic AID - MT-RNR1 (m.1555A>G), hetero and homoplasmic Leigh syndrome - MT-ATP6 (m.8993T>C) NARP - MT-ATP6 (m.8993T>G) Heteroplasmic
For each mt referral, state whether the variant can be detected in blood or muscle.
KSS - Muscle Pearson - Blood CPOE - Muscle LHON - Blood MELAS - Muscle MERFF - Blood or Muscle AID -Blood MIDD - Muscle Leigh - Blood NARP - Blood
Name some nuclear genes associated with mitochondrial DNA expression and maintenance.
How do they cause disease?
POLG, POLG2, SLC25A4
They reduce the amount of ATP available to the mitochondria, through lack of nucleoside salvage and supply, and force the cells to enter lactic acidosis.
Name some nuclear genes that indirectly cause mitochondrial disease
How do they cause disease?
SURF1 causes Leigh syndrome - affects assembly factors of the respiratory chain.
MFN2 causes CMT2A by affecting fusion.
OPA1 causes LHON by affecting fission
How can mtDNA mutations relate to ageing?
Multiple mutations accumulate over the lifetime of a person and can cause cellular dysfunction.
How can mtDNA act as a cancer biomarker?
Increased expression of mitochondrial genes is indicative of increased cellular activity. Tumours are ATP-hungry and mutations affecting the respiratory machinery is a key event in carcinogenesis.
