Role of the Deafness Dystonia Peptide 1 (DDP1) in Import of Human Tim23 into the Inner Membrane of Mitochondria

Stefan A. Paschen,Walter Neupert,Nicole Mühlenbein,Michael Brunner,Matthias F. Bauer,Uli Rothbauer,Sabine Hofmann,Klaus-Dieter Gerbitz

doi:10.1074/jbc.m105313200

Abstract

Tim8 and Tim13 of yeast belong to a family of evolutionary conserved zinc finger proteins that are organized in hetero-oligomeric complexes in the mitochondrial intermembrane space. Mutations in DDP1 (deafness dystonia peptide 1), the human homolog of Tim8, are associated with the Mohr-Tranebjaerg syndrome, a progressive neurodegenerative disorder. We show that DDP1 acts with human Tim13 in a complex in the intermembrane space. The DDP1.hTim13 complex is in direct contact with translocation intermediates of human Tim23 in mammalian mitochondria. The human DDP1.hTim13 complex complements the function of the TIM8.13 complex in yeast and facilitates import of yeast and human Tim23. Thus, the pathomechanism underlying the Mohr-Tranebjaerg syndrome may involve an impaired biogenesis of the human TIM23 complex causing severe pleiotropic mitochondrial dysfunction.

Highlights

The vast majority of mitochondrial proteins are encoded as precursors in the nuclear genome
HTim13, hTim9, hTim10a, and hTim10b as components of mitochondrial import systems is based on their sequence similarities to yeast Tim8, Tim13, Tim9, Tim10, and Tim12, respectively, structurally related zinc finger proteins identified in the mitochondrial intermembrane space of yeast [18]
Under these conditions DDP1 and hTim13 were completely released into the supernatant, demonstrating that both proteins are located in the intermembrane space

Summary

Introduction

The vast majority of mitochondrial proteins are encoded as precursors in the nuclear genome. Tim8 and Tim13 of yeast belong to a family of evolutionary conserved zinc finger proteins that are organized in hetero-oligomeric complexes in the mitochondrial intermembrane space. We analyzed the structural organization of the human zinc finger proteins DDP1 and hTim13 and their functional role in mitochondrial preprotein import.

Results

Conclusion