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Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency

Mitochondrial dysfunction is a significant factor in human disease, ranging from systemic disorders of childhood to cardiomyopathy, ischaemia and neurodegeneration. Cytochrome oxidase, the terminal enzyme of the mitochondrial respiratory chain, is a frequent target. Lower eukaryotes possess alternat...

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Autores principales: Kemppainen, Kia K., Rinne, Juho, Sriram, Ashwin, Lakanmaa, Matti, Zeb, Akbar, Tuomela, Tea, Popplestone, Anna, Singh, Satpal, Sanz, Alberto, Rustin, Pierre, Jacobs, Howard T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959817/
https://www.ncbi.nlm.nih.gov/pubmed/24293544
http://dx.doi.org/10.1093/hmg/ddt601
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author Kemppainen, Kia K.
Rinne, Juho
Sriram, Ashwin
Lakanmaa, Matti
Zeb, Akbar
Tuomela, Tea
Popplestone, Anna
Singh, Satpal
Sanz, Alberto
Rustin, Pierre
Jacobs, Howard T.
author_facet Kemppainen, Kia K.
Rinne, Juho
Sriram, Ashwin
Lakanmaa, Matti
Zeb, Akbar
Tuomela, Tea
Popplestone, Anna
Singh, Satpal
Sanz, Alberto
Rustin, Pierre
Jacobs, Howard T.
author_sort Kemppainen, Kia K.
collection PubMed
description Mitochondrial dysfunction is a significant factor in human disease, ranging from systemic disorders of childhood to cardiomyopathy, ischaemia and neurodegeneration. Cytochrome oxidase, the terminal enzyme of the mitochondrial respiratory chain, is a frequent target. Lower eukaryotes possess alternative respiratory-chain enzymes that provide non-proton-translocating bypasses for respiratory complexes I (single-subunit reduced nicotinamide adenine dinucleotide dehydrogenases, e.g. Ndi1 from yeast) or III + IV [alternative oxidase (AOX)], under conditions of respiratory stress or overload. In previous studies, it was shown that transfer of yeast Ndi1 or Ciona intestinalis AOX to Drosophila was able to overcome the lethality produced by toxins or partial knockdown of complex I or IV. Here, we show that AOX can provide a complete or substantial rescue of a range of phenotypes induced by global or tissue-specific knockdown of different cIV subunits, including integral subunits required for catalysis, as well as peripheral subunits required for multimerization and assembly. AOX was also able to overcome the pupal lethality produced by muscle-specific knockdown of subunit CoVb, although the rescued flies were short lived and had a motility defect. cIV knockdown in neurons was not lethal during development but produced a rapidly progressing locomotor and seizure-sensitivity phenotype, which was substantially alleviated by AOX. Expression of Ndi1 exacerbated the neuronal phenotype produced by cIV knockdown. Ndi1 expressed in place of essential cI subunits produced a distinct residual phenotype of delayed development, bang sensitivity and male sterility. These findings confirm the potential utility of alternative respiratory chain enzymes as tools to combat mitochondrial disease, while indicating important limitations thereof.
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spelling pubmed-39598172014-04-18 Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency Kemppainen, Kia K. Rinne, Juho Sriram, Ashwin Lakanmaa, Matti Zeb, Akbar Tuomela, Tea Popplestone, Anna Singh, Satpal Sanz, Alberto Rustin, Pierre Jacobs, Howard T. Hum Mol Genet Articles Mitochondrial dysfunction is a significant factor in human disease, ranging from systemic disorders of childhood to cardiomyopathy, ischaemia and neurodegeneration. Cytochrome oxidase, the terminal enzyme of the mitochondrial respiratory chain, is a frequent target. Lower eukaryotes possess alternative respiratory-chain enzymes that provide non-proton-translocating bypasses for respiratory complexes I (single-subunit reduced nicotinamide adenine dinucleotide dehydrogenases, e.g. Ndi1 from yeast) or III + IV [alternative oxidase (AOX)], under conditions of respiratory stress or overload. In previous studies, it was shown that transfer of yeast Ndi1 or Ciona intestinalis AOX to Drosophila was able to overcome the lethality produced by toxins or partial knockdown of complex I or IV. Here, we show that AOX can provide a complete or substantial rescue of a range of phenotypes induced by global or tissue-specific knockdown of different cIV subunits, including integral subunits required for catalysis, as well as peripheral subunits required for multimerization and assembly. AOX was also able to overcome the pupal lethality produced by muscle-specific knockdown of subunit CoVb, although the rescued flies were short lived and had a motility defect. cIV knockdown in neurons was not lethal during development but produced a rapidly progressing locomotor and seizure-sensitivity phenotype, which was substantially alleviated by AOX. Expression of Ndi1 exacerbated the neuronal phenotype produced by cIV knockdown. Ndi1 expressed in place of essential cI subunits produced a distinct residual phenotype of delayed development, bang sensitivity and male sterility. These findings confirm the potential utility of alternative respiratory chain enzymes as tools to combat mitochondrial disease, while indicating important limitations thereof. Oxford University Press 2014-04-15 2013-11-29 /pmc/articles/PMC3959817/ /pubmed/24293544 http://dx.doi.org/10.1093/hmg/ddt601 Text en © The Author 2013. Published by Oxford University Press. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Kemppainen, Kia K.
Rinne, Juho
Sriram, Ashwin
Lakanmaa, Matti
Zeb, Akbar
Tuomela, Tea
Popplestone, Anna
Singh, Satpal
Sanz, Alberto
Rustin, Pierre
Jacobs, Howard T.
Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency
title Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency
title_full Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency
title_fullStr Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency
title_full_unstemmed Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency
title_short Expression of alternative oxidase in Drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency
title_sort expression of alternative oxidase in drosophila ameliorates diverse phenotypes due to cytochrome oxidase deficiency
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959817/
https://www.ncbi.nlm.nih.gov/pubmed/24293544
http://dx.doi.org/10.1093/hmg/ddt601
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