Mitochondrial respiratory chain defects are now recognized to underlie a large number of human diseases with a spectacular variety in their phenotypic presentations. Despite progress made in the elucidation of their molecular basis, these diseases remain essentially untreatable. To date, most strategies to counteract these diseases, either in vitro or in vivo have proven unsuccessful. In humans, the respiratory chain lacks several redox active proteins long known in many micro-organisms, as well as in plants, and, as found recently, even in some metazoans. These alternative enzymes, e.g. the cyanide-insensitive alternative oxidase and the internal rotenone-insensitive NADH dehydrogenase, confer a significant flexibility to the respiratory chain, allowing it to overcome potential constraints exerted by the cell phosphorylation potential or by environmental xenobiotics. In plants, these alternative enzymes, activated by a subset of keto-acids, including pyruvate, are essentially engaged under highly reducing conditions. Because these are conditions observed in patients with respiratory chain dysfunction, we made the hypothesis that expression of these proteins might be of benefit in such situations. The observation that a functional alternative oxidase from Ciona intestinalis could be expressed in mammalian cells without obvious detrimental effect has provided a basis to develop a research programme to test the hypothesis, within an ad hoc international consortium, that this paper aims to describe. Combining research on human cells, flies and mice, the project aims, firstly, to verify that expressing these alternative enzymes is physiologically benign, useful as a tool to delineate the mechanisms of respiratory chain dysfunction and, finally, test their potential therapeutic benefit.