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.
Highlights
In mammalian mitochondria, the terminal step of electron transfer to molecular oxygen, producing water, is exclusively mediated by the cyanide-sensitive cytochrome c oxidase (COX) [1] and the electron transfer is tightly coupled to proton translocation
The energy-producing machinery is powered by the electron transfer to molecular oxygen, a mechanism whose terminal step is mediated by the cyanide-sensitive cytochrome c oxidase (COX)
Preventing the energy producing machinery blockade and excess superoxide production by means of alternative oxidase (AOX) should be of considerable interest
Summary
The terminal step of electron transfer to molecular oxygen, producing water, is exclusively mediated by the cyanide-sensitive cytochrome c oxidase (COX) [1] and the electron transfer is tightly coupled to proton translocation. Many microorganisms, and a few animals [6], a non proton-motive, cyanide-resistant AOX, can oxidize ubiquinol to produce water [7] (Figure 1A), maintaining electron transfer even when the activity of the cytochrome segment of the respiratory chain (namely complex III to IV) is limiting or unavailable [8]. Under such conditions, AOX prevents the over-reduction of ubiquinone, serving, in effect, an antioxidant role [9].
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