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university of tampere: faculty of medicine and life sciences: research: howy jacobs - mitochondrial genetics - mitochondrial biology: projects:
Lääketieteen ja biotieteiden tiedekunta FinMIT Centre of Exellence in research on  mitochondrial disease and ageing University of Tampere Institute of Biomedical Technology - IBT
Howy Jacobs - Mitochondrial Genetics - Mitochondrial Biology

ALTERNATIVES

Molecular By-pass therapy for mitochondrial dysfunction

In almost all eukaryotes, the mitochondrial respiratory chain drives oxidative phosphorylation via proton-pumping across the inner mitochondrial membrane at complexes I, III and IV. However, in most plants, protists and fungi, as well as some animals, there is an alternative, non proton-pumping  mitochondrial respiratory chain present, which can by-pass these complexes. It is believed that this allows the maintenance of cellular homeostasis under conditions where ATP levels are high, and would therefore inhibit the standard respiratory chain which is coupled to ATP synthesis. The alternative chain has been lost during the course of evolution of ‘higher animals’, i.e. vertebrates and arthropods. The reason for the loss is unknown. It may simply be that the presence of the by-pass enzymes, although they seem to be metabolically inert except under conditions where they are physiologically needed, slightly compromizes the efficiency of ATP production under conditions essential for survival, e.g. requiring rapid escape from predators or catching of prey, which are features of the lifestyle of vertebrates and arthropods. We hypothesize that the ‘re-introduction’ of the alternative chain, or specific components of it, using genetic manipulation, may confer on model metazoans the ability to resist stresses that lead to the inhibition of the standard mitochondrial respiratory chain, such as by toxins or pathological mutations. 

The alternative respiratory chain comprises two steps, each carried out by an enzyme composed of a single polypeptide (in contrast to the complexes of the standard respiratory chain that comprise dozens of polypeptides).  The alternative oxidase (AOX) by-passes complexes III and IV by shunting electrons directly from ubiquinol to molecular oxygen.  The NADH dehydrogenases of the NDE and NDI families by-pass complex I by taking electrons from NADH on to ubiquinone.  We have recloned the AOX gene from the urochordate, Ciona intestinalis and the NADH dehydrogenase gene NDI1 from yeast, in expression vectors suitable for Drosophila and for mammalian cells. Remarkably, both genes may be expressed in mammalian cells or ubiquitously in Drosophila with only minimal physiological effects. Such expression overcomes the toxicity of respiratory chain poisons or mutations in vivo, and supports a measurable by-pass respiration in vitro. AOX expression alleviates the metabolic acidosis and elevated ROS production associated with inhibition of complexes III or IV, facilitates the growth of cells carrying pathological mutations in genes for cytochrome oxidase subunits, allows flies to overcome the lethality of knockdown of complex IV subunits or the degenerative phenotypes associated with mutations that mimic the features of Parkinson’s disease. Expression of the by-pass enzymes in flies also has major effects on lifespan.

We are exploring further the physiological effects of these by-passes on model organisms, with a view to developing them eventually as wide-spectrum gene therapy tools for mitochondrial diseases in humans.

 
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Last update: 9.10.2014 13.41 Muokkaa

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