A critical evaluation of the role of alternative oxidase in the performance of strobilurin and related fungicides acting at the Qo site of complex III

Mitochondrial respiration conserves energy by linking NADH oxidation and electron-coupled proton translocation with ATP synthesis, through a core pathway involving three large protein complexes. Strobilurin fungicides block electron flow through one of these complexes (III), and disrupt energy supply. Despite an essential need for ATP throughout fungal disease development, strobilurins are largely preventative; indeed some diseases are not controlled at all, and several pathogens have quickly developed resistance. Target-site variation is not the only cause of these performance difficulties. Alternative oxidase (AOX) is a strobilurin-insensitive terminal oxidase that allows electrons from ubiquinol to bypass Complex III. Its synthesis is constitutive in some fungi but in many others is induced by inhibition of the main pathway. AOX provides a strobilurin-insensitive pathway for oxidation of NADH. Protons are pumped as electrons flow through Complex I, but energy conservation is less efficient than for the full respiratory chain. Salicylhydroxamic acid (SHAM) is a characteristic inhibitor of AOX, and several studies have explored the potentiation of strobilurin activity by SHAM. We present a kinetic-based model which relates changes in the extent of potentiation during different phases of disease development to a changing importance of energy efficiency. The model provides a framework for understanding the varying efficacy of strobilurin fungicides. In many cases, AOX can limit strobilurin effectiveness once an infection is established, but is unable to interfere significantly with strobilurin action during germination. A less stringent demand for energy efficiency during early disease development could lead to insensitivity towards this class of fungicides. This is discussed in relation to Botrytis cinerea, which is often poorly controlled by strobilurins. Mutations with a similar effect may explain evidence implicating AOX in resistance development in normally well-controlled plant pathogens, such as Venturia inaequalis.