Import of proteins into mitochondria: A novel pathomechanism for progressive neurodegeneration

The vast majority of mitochondrial proteins are encoded as precursors by th e nuclear genome. A major aspect of mitochondrial biogenesis is therefore t he transfer of nuclear-encoded, cytosplasmically synthesized precursor prot eins across and into the mitochondrial membranes. During the past years the use of simple model organisms such as the yeasts S. cerevisiae and N. cras sa has helped considerably to identify and unravel the structure and functi on of a substantial number of components involved in targeting of nuclear-e ncoded preproteins to mitochondria. Several pathways and a number of compon ents were characterized that are involved in guiding mitochondrial preprote ins to their specific sites of function. In particular, import of nuclear- encoded precursor proteins into and across the mitochondrial inner membrane is mediated by two distinct translocases, the TIM23 complex and the TIM22 complex. Both TIM complexes cooperate with the general preprotein transloca se of the outer membrane, TOM complex. The TIM complexes differ in the thei r substrate specificity. While the TIM23 complex mediates import of preprot eins with a positively charged matrix targeting signal, the TIM22 complex f acilitates the insertion of a class of hydrophobic proteins with internal t argeting signals into the inner membrane. Most recently the rapid progress of research has allowed elucidation of a new mitochondrial disease on the m olecular level. This rare X-linked progressive neurodegenerative disorder, named Mohr-Tranebjaerg (MT syndrome), is caused by mutations in the DDP1 ge ne and includes sensorineural deafness, blindness, mental retardation and a complex movement disorder. The analysis of the novel pathomechanism is bas ed on the homology of the affected DDP1 protein to a family of conserved ye ast components acting along the TIM22 pathway. This contribution briefly su mmarizes the current knowledge of the pathways of protein import and propos es a mechanism to explain how defective import leads to neurodegeneration.