Non-Mendelian Inheritance III

Non-Mendelian Inheritance III: Mitochondrial Inheritance

Mitochondrial Ox/Phos

the electron transport chain is located in the inner mito membrane; Ox/Phos produces ATP

the five enzyme complexes of the system are coded for by both nuclear and mitochondrial DNA

mitochondrial dysfunction could be of nuclear or mitochondrial origin

number of mtDNA genes encoding for each complex:

complex 1: 7
complex 2: 0
complex 3: 1
complex 4: 3
complex 5: 2

mitochondrial dysfunction is more readily apparent in high-energy demand tissues:

i.e. heart, kidney, skeletal muscle, CNS, etc

Structure and Function of Mitochondrial Genome

mtDNA: no introns; circular; two strands - heavy and light;

approx. 16568 bp long; no histones

Heavy chain Þ 12 polypeptides, 14 tRNAs, 2 rRNAs

Light chain Þ 1 polypeptide, 8 tRNAs, 0 rRNAs

transcription is asynchronous; begins at heavy strand origin, when

polymerase reaches light strand origin, transcribes light strand in opposite direction

transcription is performed by a mito specific RNA polymerase and regulatory proteins; genetic code is slightly different

mtDNA uses its own tRNA

Þ nuclear proteins cannot read mtDNA (vice versa)

mutations: mtDNA replication machinery is incapable of repair

Þ replication errors are 5-10x higher than in nuclear DNA

also, high oxygen content in mito predisposes to free radical damage

most mutations are large deletions; point mutations have been linked to human disease

Principles of Mitochondrial Inheritance

mtDNA is only inherited from the mother Þ matrilineal inheritance

there are 2-10 copies of mt DNA per mito = 20 - 1000 per cell

because of high mutation rate, can have many different copies of mtDNA in a single cell
heteroplasmy: different forms of mtDNA per single cell (80% heteroplasmy = 80% mutant DNA)
homoplasmy: single form of mtDNA per single cell
intragenomic complementation: result of heteroplasmy: wild-type mtDNA may complement mutant mtDNA

replicative segregation: shift in the proportion of wild and mutant types of mtDNA resulting from cell division

segregation is random, but distribution may change; analogous to genetic drift in population genetics

Rules of Mitochondrial Inheritance

mitochondrial inheritance is matrilineal

an affected man will never pass the trait on to his children

the phenotype of the mitochondrial trait will show significant variability of expression based on the tissue affected

an affected individual’s phenotype may worsen over time

Expression of mtDNA mutations

germline mutations can lead to maternally transmitted diseases

unequal partitioning can result in variable expression

somatic mutations can lead to degenerative disease especially if mutant DNA accumulats in tissues with high-energy requirements

mtDNA mutations are expressed as defects in respiratory chain subunits or mtRNA

end result is decreased ox/phos and energy metabolism

clinical manifestations of mutant mtDNA depend on how well the mutant is complemented and on the energy requirements of the tissue (i.e. decreased mito activity will be noticed sooner in skeletal muscle)

major manefestations: muscle disease, cardiac disease, neurological disease, endocrine abnormalities

Mitochondrial Diseases

can result from mtDNA or nDNA mutations that encode for mito proteins can result in mito disease

MERRF: A Þ G point mutation in tRNA Þ muscle respiratory chain defects; childhood presentation

results in myoclonic epilepsy with ragged red muscle fibers; ataxia; hypotonia
threshold level: 80-90% heteroplasmy before symptoms show up

MELAS: A Þ G point mutation in tRNA; childhood presentation

results in mitochondrial myoencephalopathy; lactic acidosis; stroke-like symptoms
multisystem abnormalities; progressive dementia