MITOCHONDRIAL GENETICSMITOCHONDRIAL GENETICS

Origin of MitochondriaOrigin of MitochondriaEndosymbiont TheoryEndosymbiont Theory

• Similar size to certain free-living bacteria

• Similar chromosome & cytoplasm to bacteria

• Similar ribosomes to bacteria

• Similar cell division to bacteria

• Independent replication & gene expression

Nuclear (Cellular) ChromosomesNuclear (Cellular) Chromosomes

3.2 billion total nucleotide pairs3.2 billion total nucleotide pairs

MitochondrialMitochondrialChromosomesChromosomes

2-10 @ per mito2-10 @ per mito1000-10000 per cell1000-10000 per cell

0.32-1.6 billion0.32-1.6 billion total nucleotide pairstotal nucleotide pairs

Genetically Genetically Controlled Controlled ProcessesProcesses

in Mitochondriain Mitochondria

• 13 genes for respiratory chain proteins• Subunits of the ATPase complex

• Subunits for the NADH-dehydrogenase complex

• 22 genes for tRNAs

• 2 genes for rRNAs

• Maintenance of cellular energy levels

Ataxia v. AtaxiaAtaxia v. Ataxia

Human Mitochondria

• 2-10 chromos per mito• 13 protein-encoding regions• 3 subunits of cytochrome c oxidase

complex• Cytochrome b complex• 2 subunits of the ATPase complex• 60% occupied by six subunits of

NADH dehydrogenase complex• 22 tRNAs• 2 rRNAs• other

Stability of Mitochondrial DNAStability of Mitochondrial DNA

• Mutatation rate 10X higher than nuclear DNA

• Mutations generated by oxidation by-products

• No protective histones

• Ineffective DNA repair

• Typically point mutations or deletions

• Tolerance for deletions variable

• Some deletions recurring in unrelated patients

Mitochondrial DiseasesMitochondrial DiseasesGeneral CharacteristicsGeneral Characteristics

• Penetrance usually complete (100%)• Expressivity highly variable• Age of onset variable• Frequently limited to specific tissues• Usually appear as reduced muscle strength

together with degeneration of other tissues• Affects organs with high energy requirements:

brain, heart, skeletal muscle, eye, ear, liver, pancreas, and kidney

Some Mitochondrial DiseasesSome Mitochondrial Diseases

• Kearns-Sayre syndromeopthalmoplegia, retinal degeneration, cardiomyopathy

• Lactic-Acidosis-Encephalomyopathy-Stroke syndrome

• Neurogenic muscle weakness with ataxia and retinitis pigmentosa syndrome

• Pearson syndromebone marrow and pancreas failure

• Diabetes-deafness syndrome

Maternal Transmittance of Mitochondrial Disease

heteroplasmyheteroplasmy

Mitochondrial DiseasesMitochondrial DiseasesGeneral CharacteristicsGeneral Characteristics

• Penetrance usually complete (100%)• Expressivity highly variable• Age of onset variable• Frequently limited to specific tissues• Usually appear as reduced muscle strength

together with degeneration of other tissues• Affects organs with high energy requirements:

brain, heart, skeletal muscle, eye, ear, liver, pancreas, and kidney

At the course download site:

mitogenetics.ppt