technical knockout, a Drosophila model of mitochondrial deafness

Mutations in mtDNA-encoded components of the mitochondrial translational ap paratus are associated with diverse pathological states in humans, notably sensorineural deafness. To develop animal models of such disorders, we have manipulated the nuclear gene for mitochondrial ribosomal protein S12 in Dr osophila (technical knockout, tko). The prototypic mutant tko(25t) exhibits developmental delay, bang sensitivity, impaired male courtship, and defect ive response to sound. Oil the basis of a transgenic reversion test, these phenotypes are attributable to a single Substitution (L85H) at a conserved residue of the tko protein. The mutant is hypersensitive to doxycyclin, an antibiotic that selectively inhibits mitochondrial protein synthesis, and m utant larvae have greatly diminished activities of mitochondrial redox enzy mes and decreased levels of mitochondrial small-subunit rRNA. A second muta tion in the tko gene, Q116K, which is predicted to impair the accuracy of m itochondrial translation, results in the completely different phenotype of recessive female sterility, based oil three independent transgenic insertio ns. We infer that the tko(25t) mutant provides a model of mitochondrial hea ring impairment resulting from a quantitative deficiency of mitochondrial t ranslational capacity.