Martha Kotsifas, Christian Barth, Arturo de Lozanne, Sui T. Lay, and Paul R. Fisher

J. Muscle Res. & Cell Motility. Dictyostelium Special Issue.

Abstract

Mitochondrial diseases are frequently caused by mutations in a subpopulation of the mitochondrial genomes in each cell (a state called heteroplasmy). In humans they often present clinically as degenerative, neuromuscular disorders. Mitochondrial function can also be impaired by mutations affecting nuclear-encoded mitochondrial proteins. One such protein, required for correct folding in the organelle of both mitochondrially- and nuclear-encoded proteins is chaperonin 60. Here we report that antisense RNA inhibition of expression of chaperonin 60 impairs signal transduction for phototaxis in the multicellular slug stage of Dictyostelium discoideum. Independent, stable transformants were isolated with differing levels of antisense inhibition of chaperonin 60 expression, depending upon the number of copies of an antisense RNA-expressing plasmid in the genome. Phototaxis (and thermotaxis) was severely impaired in all antisense transformants, while growth and morphogenesis were markedly defective only in those with higher levels of antisense inhibition. This mimics the previously observed phenotypes caused by heteroplasmic disruption of the mitochondrial large subunit rRNA gene (Wilczynska, Z., Barth, C., Fisher, PR. 1997, Biochem. Biophys. Res. Comm., 234:39-43). Our results suggest that, regardless of the nature of the underlying genetic defect, mitochondrial deficiency impairs signal transduction more sensitively than other cellular activities. This may explain why human mitochondrial diseases present most commonly as central nervous system, muscle and cardiac disorders.