Human deafness dystonia syndrome is a mitochondrial disease

TLDR

The human deafness dystonia syndrome is caused by mutations in the DDP protein, whose function was previously unknown. We demonstrate that DDP is a mitochondrial intermembrane space protein homologous to Tim8p and related Tim proteins, and that the syndrome represents a novel mitochondrial disease likely caused by a defective protein‑import system.

Abstract

The human d eafness d ystonia syndrome results from the mutation of a p rotein (DDP) of unknown function. We show now that DDP is a mitochondrial protein and similar to five small proteins (Tim8p, Tim9p, Tim10p, Tim12p, and Tim13p) of the yeast mitochondrial intermembrane space. Tim9p, Tim10p, and Tim12p mediate the import of metabolite transporters from the cytoplasm into the mitochondrial inner membrane and interact structurally and functionally with Tim8p and Tim13p. DDP is most similar to Tim8p. Tim8p exists as a soluble 70-kDa complex with Tim13p and Tim9p, and deletion of Tim8p is synthetically lethal with a conditional mutation in Tim10p. The deafness dystonia syndrome thus is a novel type of mitochondrial disease that probably is caused by a defective mitochondrial protein-import system.