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Louise Williams 15/11/2007

In families with mitochondrial disorders, different family members can present with different clinical manifestations. Discuss this statement with respect to the principles defining mitochondrial genetics. Louise Williams 15/11/2007. Overview. What are mitochondria? What do mitochondria do?

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Louise Williams 15/11/2007

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  1. In families with mitochondrial disorders, different family members can present with different clinical manifestations.Discuss this statement with respect to the principles defining mitochondrial genetics. Louise Williams 15/11/2007

  2. Overview • What are mitochondria? • What do mitochondria do? • Mitochondrial genes/genome • Mitochondrial inheritance • Mitochondrial disorders • Genotype/phenotype correlations in mitochondrial disease.

  3. What are mitochondria? • Mitochondria are semi-autonomous, self reproducing organelles that exist in the cytoplasm of eukaryotic cells. • Each cell can contain hundreds of mitochondria.

  4. What do mitochondria do? • Mitochondria are the ‘powerhouses’ of aerobic eukaryotic cells: • Within mitochondria, organic nutrients are oxidised by molecular oxygen and the energy released is used to create ATP (oxidative phosphorylation). • This process is catalysed by a series of 5 membrane bound protein complexes making up the mitochondrial respiratory chain. • The ATP can diffuse to all parts of the cell and donate its stored energy (by hydrolysis to ADP) to drive numerous other cellular functions.

  5. Mitochondrial genome • Each mitochondrion contains between 2 and 10 copies of the mitochondrial genome. • The mitochondrial genome contains 13 of the essential peptides from the OXPHOS pathway along with all of the RNA machinery necessary for translation (tRNA and rRNA). • The other protein subunits making up the respiratory chain are encoded for by nuclear genes and transported into the mitochondria.

  6. Mitochondrial genome 2 • In most individuals all of the copies of the mitochondrial genome will be identical – this is known as homoplasmy. • In individuals with mitochondrial disorders, some copies of the genome will contain a mutation – this is known as heteroplasmy. • The level of heteroplasmy can vary between individuals (even within a family), and in different cell types within an individual. • Mutations can be point mutations or large rearrangements of the mitochondrial genome or missense mutations in other genes of the OXPHOS pathway.

  7. Mitochondrial genome 3 • The oxidative phosphorylation machinery does not need to be operating at 100% for cells or individuals to remain healthy, but there is a minimum level which needs to be operational for each cell type. • This is known as the ‘threshold’ – or the level of heteroplasmy (mutant mitochondrial DNA) that can be tolerated before disease occurs. • In tissues highly dependant on oxidative phosphorylation (e.g. skeletal muscle) this will be lower, and can vary between tissue types even for the same mutation.

  8. Mitochondrial Inheritance • Mitochondria are only passed from mother to offspring – there is no paternal transmission. • The level of heteroplasmy of a mitochondrial mutation can alter at this point due to a ‘bottleneck’ effect. • This means that offspring can be more (higher mutant load) or less (lower mutant load) severely affected than their mother.

  9. The ‘Bottleneck’ effect.

  10. Mitochondrial disorders • Mitochondrial diseases are a heterogeneous group of disorders that arise as a result of dysfunctions of the respiratory chain. • These can be due to mutations in the mitochondrial or nuclear genes involved in this process. • Some disorders affect only one tissue type, while others are multi-system disorders, often including neurological features. • Individuals may display a cluster of clinical features that fall into a discrete clinical syndrome (e.g. KSS, CPEO, MELAS, MERRF, NARP, LHON or LS).

  11. Genotype/Phenotype correlation in mitochondrial disorders • There is very little genetype/phenotype correlation in mitochondrial disorders, but disorders affecting only 1 cell type tend to be associated with homoplasmic mutations. • LHON (Lebers hereditary optic neuorpathy) • This disorder is unusual as not all individuals in a family carrying a mutation will develop the disorder - ~50% of males and ~10% of females will develop symptoms. • This is though to be due to some external factor (possible a nuclear genetic factor) modifying the expression of the disease. • This is also thought to be the case in SNHL.

  12. Genotype/Phenotype correlation in mitochondrial disorders 2 • The level of heteroplasmy can vary in different cell types. • This is due to random partitioning at mitosis which means some cells have more or less mutant DNA. • This can lead to one mutation causing several different disorders, for example the 3243 mutation. • Different presentations can also occur depending on level of heteroplasmy in one cell type, for example in NARP/Leigh syndrome.

  13. Take home points • ‘bottleneck’ effect during oogenesis means level of heteroplasmy can change between generations. • ‘External factors’ can also influence development of a phenotype in homoplasmic mutation carriers. • ‘Random mitotic segregation’ of mitochondria can mean some tissues have higher or lower levels of heteroplasmy.

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