The role of the TIM8-13 complex in the import of Tim23 into mitochondria

Tim8 and Tim13 are non-essential, conserved proteins of the mitochondrial i ntermembrane space, which are organized in a hetero-oligomeric complex. The y are structurally related to Tim9 and Tim10, essential components of the i mport machinery for mitochondrial carrier proteins. Here me show that the T IM8-13 complex interacts with translocation intermediates of Tim23, which a re partially translocated across the outer membrane but not,vith fully impo rted or assembled Tim23. The TIM8-13 complex binds to the N-terminal or int ermediate domain of Tim23. It traps the incoming precursor in the intermemb rane space thereby preventing retrograde translocation. The TIM18-13 comple x is strictly required for import of Tim23 under conditions when a low memb rane potential exists in the mitochondria. The human homologue of Tim8 is e ncoded by the DDP1 (deafness/dystonia peptide 1) gene, which is associated with the Mohr-Tranebjaerg syndrome (MTS), a progressive neurodegenerative d isorder leading to deafness. It is demonstrated that import of human Tim23 is dependent on a high membrane potential. A mechanism to explain the patho logy of MTS is discussed.