Expression of the alternative oxidase mitigates beta-amyloid production and toxicity in model systems.
Mitochondrial dysfunction has been widely associated with the pathology of Alzheimer's disease, but there is no consensus on whether it is a cause or consequence of disease, nor on the precise mechanism(s). We addressed these issues by testing the effects of expressing the alternative oxidase AOX from Ciona intestinalis, in different models of AD pathology. AOX can restore respiratory electron flow when the cytochrome segment of the mitochondrial respiratory chain is inhibited, supporting ATP synthesis, maintaining cellular redox homeostasis and mitigating excess superoxide production at respiratory complexes I and III. In human HEK293-derived cells, AOX expression decreased the production of beta-amyloid peptide resulting from antimycin inhibition of respiratory complex III. Because hydrogen peroxide was neither a direct product nor substrate of AOX, the ability of AOX to mimic antioxidants in this assay must be indirect. In addition, AOX expression was able to partially alleviate the short lifespan of Drosophila models neuronally expressing human beta-amyloid peptides, whilst abrogating the induction of markers of oxidative stress. Our findings support the idea of respiratory chain dysfunction and excess ROS production as both an early step and as a pathologically meaningful target in Alzheimer's disease pathogenesis, supporting the concept of a mitochondrial vicious cycle underlying the disease.
INSERM UMR 1141 and Université Paris 7, Faculté de Médecine Denis Diderot, Hôpital Robert Debré, 48, Boulevard Sérurier, 75019 Paris, France; American University of Beirut Medical Center, Department of Pathology and Laboratory Medicine, Cairo Street, Hamra, Beirut, Lebanon.
Riyad
R
El-Khoury
BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
Eveliina
E
Kaulio
BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
Katariina A
KA
Lassila
Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK and MedImmune Ltd, Aaron Klug Building, Granta Park, Cambridge CB21 6GH, UK.
Damian C
DC
Crowther
BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland; Institute of Biotechnology, FI-00014 University of Helsinki, Finland. Electronic address: howard.jacobs@helsinki.fi.
Howard T
HT
Jacobs
INSERM UMR 1141 and Université Paris 7, Faculté de Médecine Denis Diderot, Hôpital Robert Debré, 48, Boulevard Sérurier, 75019 Paris, France.
Pierre
P
Rustin
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D000968:Antimycin A / Q000008:administration & dosage / Q000031:analogs & derivatives; D000975:Antioxidants / Q000378:metabolism; D002938:Ciona intestinalis / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D010940:Plant Proteins / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D000099188:Alternative Oxidase
D016229:Amyloid beta-Peptides; D000968:Antimycin A; D000975:Antioxidants; D042967:Electron Transport Complex I; D003576:Electron Transport Complex IV; D006861:Hydrogen Peroxide; D024101:Mitochondrial Proteins; D010088:Oxidoreductases; D010940:Plant Proteins; D017382:Reactive Oxygen Species; D013481:Superoxides; D000099188:Alternative Oxidase; C032456:antimycin
Alzheimer's disease; Dementia; Mitochondria; Neurodegeneration; Oxidative stress