Fig. 8.

Cofilin function links the control of mitochondrial function to multi-drug resistance. Mutations that lie within the known actin binding face (Class III mutations), which are labelled in yellow, lead to fragmented mitochondria. Mutations of residues (Class II mutations) that lie outside of the defined actin-interacting face, demarcated by the blue dotted line, were found to stabilise F-actin during nutrient depletion. Actin aggregation in these mutants triggered the inappropriate activation of Ras, which in turn leads to the accumulation of ROS and cell death. The loss of charge in regions not associated with actin regulation results in an apparently Ras–cAMP–PKA-independent post-transcriptional upregulation of mitochondrial function. The altered mitochondrial function leads to a multi-drug resistance response that is dependent upon PDR1 and to the upregulation of peroxisomal fatty acid β-oxidation, which might support elevated levels of respiration. We also postulate that elevated mitochondrial function might provide the ATP required to fuel drug pump activity.