Jacobs 2015 Abstract MiP2015

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Alternative respiratory chain enzymes in research and therapy.

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Jacobs H (2015)

Event: MiP2015

In order to develop a potential therapeutic strategy for mitochondrial disorders, we have transferred genes for non proton-motive alternative respiratory chain enzymes from lower eukaryotes to model organisms, aiming to buffer metabolic stress in the OXPHOS system. Our studies have focused on both widespread and tissue-restricted expression of the alternative oxidase (AOX) from the tunicate Ciona intestinalis in human cells, mouse and Drosophila, as well as expression of the single-subunit NADH dehydrogenases from Ciona (NDX) and yeast (Ndi1). We were able to generate a robust resistance to OXPHOS toxins at the organellar, cellular and whole organism level. Extensive phenotyping of ubiquitously expressing AOX transgenic flies or mice, or NDX transgenic flies, revealed almost no significant deviations from thw wild-type phenotype under normal physiological conditions.

We determined that AOX is able to compensate for the deleterious organismal phenotypes, up to lethality and including neurodegeneration and locomotor defect, caused by deficiency of cytochrome oxidase in different tissues of Drosophila. Similarly, NDX or Ndi1 partially compensated for complex I deficiency. AOX also compensated phenotypes associated with deficiency of dj-1β, the fly homologue of a human Parkinson’s disease gene, and expression of human β-amyloid peptides in a Drosophila model of Alzheimer’s disease.

However, in our standard Drosophila model of mitochondrial disease, tko25t, AOX expression produced no detectable benefit, whilst Ndi1 expression was synthetically lethal with the tko25t mutation.

Even more surprisingly, AOX (but not Ndi1) was able partially to compensate for several phenotypes not previously associated with mitochondrial dysfunction. These include a range of developmental dysmporphologies caused by over-expression of a steroid-binding transcription factor or by deranged cell signalling. Although we do not yet have convincing data to explain these phenomena mechanistically, our findings suggest that mitochondrial dysfunction may play an even wider role in cellular and organismal pathophysiology than hitherto appreciated, and/or that AOX has other properties besides its canonical role as a ubiquinol oxidase.


Labels: MiParea: nDNA;cell genetics, mt-Medicine, mt-Awareness  Pathology: Alzheimer's, Neurodegenerative, Parkinson's  Stress:Mitochondrial disease  Organism: Human, Mouse, Drosophila, Other invertebrates 


Enzyme: Complex IV;cytochrome c oxidase 



Event: A3, Oral  MiP2015 

Affiliations

Inst Biotechn, Univ Helsinki, Finland. - howard.jacobs@helsinki.fi

Acknowledgements

I thank current and former members of my research team whose work I here present, notably Marten Szibor, Eric Dufour, Kia and Esko Kemppainen, Ana Andjelkovic, Suvi Vartiainen, Marcos Oliveira, Alberto Sanz, Giuseppe Cannino, Cagri Yalgin, Daniel Fernandez-Ayala, Eveliina Kaulio and Dmytro Gospodaryov, together with collaborators Pierre Rustin, Thomas Braun, Ines Anderl, Dan Hultmark and colleagues at the German Mouse Clinic.