Alternative oxidase expression in the mouse enables bypassing cytochrome c oxidase blockade and limits mitochondrial ROS overproduction

PLoS Genet. 2013;9(1):e1003182. doi: 10.1371/journal.pgen.1003182. Epub 2013 Jan 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ciona intestinalis / genetics
  • Electron Transport / genetics
  • Electron Transport / physiology
  • Electron Transport Complex IV* / antagonists & inhibitors
  • Electron Transport Complex IV* / genetics
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mice, Transgenic
  • Mitochondria* / genetics
  • Mitochondria* / metabolism
  • Mitochondria* / physiology
  • Oxidation-Reduction
  • Oxidative Phosphorylation
  • Oxidoreductases* / genetics
  • Oxidoreductases* / metabolism
  • Reactive Oxygen Species* / metabolism
  • Superoxides / metabolism
  • Ubiquinone / analogs & derivatives
  • Ubiquinone / metabolism

Substances

  • Reactive Oxygen Species
  • Superoxides
  • Ubiquinone
  • Oxidoreductases
  • duroquinol oxidase
  • Electron Transport Complex IV
  • ubiquinol

Grant support

This work was funded by INSERM (Institut National de la Santé et de la Recherche Médicale) and the European Research Council (grant to HTJ). RE-K received support from Anr AifInter. MR, PB, and PR received support from AMMi (Association contre les Maladies Mitochondriales), AFM (Association Française contre les Myopathies), AFAF (Association Française contre l'Ataxie de Friedreich), FRM (Fondation pour la Recherche Médicale), and ANR projects MitOxy and AifInter. HTJ's research is also supported by Academy of Finland, Sigrid Juselius Foundation, and Tampere University Hospital Medical Research Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.