Subpopulations of mutant mitochondria appear to play important roles in degenerative processes associated with aging and are characteristic of many mitochondrial diseases. We have generated mutants carrying plasmid insertions in theDictyostelium discoideummitochondrial genome and have shown that phototaxis and thermotaxis in these mutants is more sensitive than growth and division to the presence of a subpopulation of defective mitochondria. This could result from direct impairment of a mitochondrial role in signal transduction, or indirectly from the effects of energy depletion. Either way, signal transduction may be the first cellular activity to be compromised by the accumulation of defective mitochondria in age-related tissue dysfunction and in mitochondrial disease.