Expression of the Ciona intestinalis alternative oxidase (AOX) in Drosophila complements defects in mitochondrial oxidative phosphorylation.
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.
Fernandez-Ayala
Daniel J M
DJ
Institute of Medical Technology, Tampere University Hospital, University of Tampere, 33014 Tampere, Finland.
Sanz
Alberto
A
Vartiainen
Suvi
S
Kemppainen
Kia K
KK
Babusiak
Marek
M
Mustalahti
Eero
E
Costa
Rodolfo
R
Tuomela
Tea
T
Zeviani
Massimo
M
Chung
Jongkyeong
J
O'Dell
Kevin M C
KM
Rustin
Pierre
P
Jacobs
Howard T
HT
D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D002938:Ciona intestinalis / Q000201:enzymology; D004330:Drosophila / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010940:Plant Proteins; D011190:Potassium Cyanide / Q000494:pharmacology; D000071617:Protein Deglycase DJ-1; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099188:Alternative Oxidase
D000968:Antimycin A; D029721:Drosophila Proteins; D003576:Electron Transport Complex IV; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D010088:Oxidoreductases; D010940:Plant Proteins; D011190:Potassium Cyanide; D000071617:Protein Deglycase DJ-1; D017382:Reactive Oxygen Species; D000099188:Alternative Oxidase; C092928:Surf-1 protein; C032456:antimycin; C439315:CYPE protein, Drosophila; C506879:DJ-1beta protein, Drosophila