Expression of the Ciona intestinalis alternative oxidase (AOX) in Drosophila complements defects in mitochondrial oxidative phosphorylation

Daniel J M Fernandez-Ayala; Alberto Sanz; Suvi Vartiainen; Kia K Kemppainen; Marek Babusiak; Eero Mustalahti; Rodolfo Costa; Tea Tuomela; Massimo Zeviani; Jongkyeong Chung; Kevin M C O'Dell; Pierre Rustin; Howard T Jacobs

doi:10.1016/j.cmet.2009.03.004

Expression of the Ciona intestinalis alternative oxidase (AOX) in Drosophila complements defects in mitochondrial oxidative phosphorylation

Cell Metab. 2009 May;9(5):449-60. doi: 10.1016/j.cmet.2009.03.004.

Authors

Daniel J M Fernandez-Ayala¹, Alberto Sanz, Suvi Vartiainen, Kia K Kemppainen, Marek Babusiak, Eero Mustalahti, Rodolfo Costa, Tea Tuomela, Massimo Zeviani, Jongkyeong Chung, Kevin M C O'Dell, Pierre Rustin, Howard T Jacobs

Affiliation

¹ Institute of Medical Technology, Tampere University Hospital, University of Tampere, 33014 Tampere, Finland.

PMID: 19416715
DOI: 10.1016/j.cmet.2009.03.004

Abstract

Defects in mitochondrial OXPHOS are associated with diverse and mostly intractable human disorders. The single-subunit alternative oxidase (AOX) found in many eukaryotes, but not in arthropods or vertebrates, offers a potential bypass of the OXPHOS cytochrome chain under conditions of pathological OXPHOS inhibition. We have engineered Ciona intestinalis AOX for conditional expression in Drosophila melanogaster. Ubiquitous AOX expression produced no detrimental phenotype in wild-type flies. However, mitochondrial suspensions from AOX-expressing flies exhibited a significant cyanide-resistant substrate oxidation, and the flies were partially resistant to both cyanide and antimycin. AOX expression was able to complement the semilethality of partial knockdown of both cyclope (COXVIc) and the complex IV assembly factor Surf1. It also rescued the locomotor defect and excess mitochondrial ROS production of flies mutated in dj-1beta, a Drosophila homolog of the human Parkinson's disease gene DJ1. AOX appears to offer promise as a wide-spectrum therapeutic tool in OXPHOS disorders.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antimycin A / analogs & derivatives
Antimycin A / pharmacology
Ciona intestinalis / enzymology
Drosophila / metabolism*
Drosophila Proteins / genetics
Drosophila Proteins / metabolism
Electron Transport Complex IV / genetics
Electron Transport Complex IV / metabolism
Enzyme Inhibitors / pharmacology
Gene Knockdown Techniques
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mitochondria / enzymology*
Mitochondria / metabolism
Mitochondrial Proteins / genetics
Mitochondrial Proteins / metabolism
Nerve Tissue Proteins / metabolism
Oxidative Phosphorylation*
Oxidoreductases / biosynthesis*
Oxidoreductases / genetics
Oxidoreductases / metabolism
Phenotype
Plant Proteins
Potassium Cyanide / pharmacology
Protein Deglycase DJ-1
Reactive Oxygen Species / metabolism

Substances

Drosophila Proteins
Enzyme Inhibitors
Membrane Proteins
Mitochondrial Proteins
Nerve Tissue Proteins
Plant Proteins
Reactive Oxygen Species
Surf-1 protein
antimycin
Antimycin A
Oxidoreductases
alternative oxidase
CYPE protein, Drosophila
Electron Transport Complex IV
DJ-1beta protein, Drosophila
Protein Deglycase DJ-1
Potassium Cyanide

Grants and funding

GGP07019/TI_/Telethon/Italy