title: Alternative oxidase expression in the mouse enables bypassing cytochrome c oxidase blockade and limits mitochondrial ROS overproduction.
abstract: Cyanide-resistant non-phosphorylating respiration is known in mitochondria from plants, fungi, and microorganisms but is absent in mammals. It results from the activity of an alternative oxidase (AOX) that conveys electrons directly from the respiratory chain (RC) ubiquinol pool to oxygen. AOX thus provides a bypath that releases constraints on the cytochrome pathway and prevents the over-reduction of the ubiquinone pool, a major source of superoxide. RC dysfunctions and deleterious superoxide overproduction are recurrent themes in human pathologies, ranging from neurodegenerative diseases to cancer, and may be instrumental in ageing. Thus, preventing RC blockade and excess superoxide production by means of AOX should be of considerable interest. However, because of its energy-dissipating properties, AOX might produce deleterious effects of its own in mammals. Here we show that AOX can be safely expressed in the mouse (MitAOX), with major physiological parameters being unaffected. It neither disrupted the activity of other RC components nor decreased oxidative phosphorylation in isolated mitochondria. It conferred cyanide-resistance to mitochondrial substrate oxidation and decreased reactive oxygen species (ROS) production upon RC blockade. Accordingly, AOX expression was able to support cyanide-resistant respiration by intact organs and to afford prolonged protection against a lethal concentration of gaseous cyanide in whole animals. Taken together, these results indicate that AOX expression in the mouse is innocuous and permits to overcome a RC blockade, while reducing associated oxidative insult. Therefore, the MitAOX mice represent a valuable tool in order to investigate the ability of AOX to counteract the panoply of mitochondrial-inherited diseases originating from oxidative phosphorylation defects.
authors.affiliation: Inserm, UMR 676, Hôpital Robert Debré, Paris, France.
authors.forename: Riyad
authors.initials: R
authors.lastname: El-Khoury
authors.forename: Eric
authors.initials: E
authors.lastname: Dufour
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Rak
authors.forename: Nelina
authors.initials: N
authors.lastname: Ramanantsoa
authors.forename: Nicolas
authors.initials: N
authors.lastname: Grandchamp
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Csaba
authors.forename: Bertrand
authors.initials: B
authors.lastname: Duvillié
authors.forename: Paule
authors.initials: P
authors.lastname: Bénit
authors.forename: Jorge
authors.initials: J
authors.lastname: Gallego
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.forename: Chamsy
authors.initials: C
authors.lastname: Sarkis
authors.forename: Howard T
authors.initials: HT
authors.lastname: Jacobs
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
mesh_terms: D000818:Animals; D002938:Ciona intestinalis / Q000235:genetics; D004579:Electron Transport / Q000235:genetics / Q000502:physiology; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D013481:Superoxides; D014451:Ubiquinone; D010088:Oxidoreductases; C020094:duroquinol oxidase; D003576:Electron Transport Complex IV; C003741:ubiquinol