May 21, 2004
Title: How are proteins imported into the mitochondrion?
Dr. Carla Koehler
UCLA, Department of Chemistry and Biochemistry
location within the cell. Of all
the organelles in a mammalian cell, the mitochondrion is the most
complex because two membranes must be crossed. In addition to
the metabolic role, the mitochondrion is a key player in many
cellular processes including apoptosis, metal ion homeostasis
and aging. My research focuses on mitochondrial biogenesis, particularly
the mechanism by which proteins are imported into the mitochondrial
The mitochondrion contains several protein import and export pathways. The general protein import pathway for precursors carrying a cleavable, N-terminal targeting sequence has been well-characterized. The coordinated action of the translocase of the outer membrane (TOM) and the Tim23p/Tim17p translocase of the inner membrane (TIM23) mediates passage of the precursor from the cytoplasm to the matrix. Components of the TOM and TIM complexes are integral membrane proteins, and many are essential for cell viability. In the TOM complex of yeast mitochondria, Tom20, 22, 37, and 70 are receptors, mediating transfer of the precursor from cytosolic chaperones to the TOM channel consisting of Tom5, 6, 7, and 40. Tim23 of the inner membrane contains a hydrophilic domain that functions as a receptor for the precursor as it emerges from the TOM channel. The precursor passes through the TIM23 channel (Tim23 and Tim17) and ATP hydrolysis by the translocation motor of Tim44, mHsp70, and mGrpE completes translocation.
Many precursors lack a cleavable targeting sequence, carrying instead their targeting and sorting information within the "mature" part of the polypeptide chain. This category of proteins includes at least 34 members of the mitochondrial carrier family, which span the membrane six times, as well as numerous other inner membrane proteins, including the import components themselves. The TIM22 pathway mediates import of these proteins. Components include the tiny Tim proteins of the intermembrane space (Tim8, Tim9, Tim10, Tim12, and Tim13) and the inner membrane proteins Tim18, Tim22, and Tim54 (9, 14). The tiny Tim proteins act as putative chaperones to guide unfolded inner membrane proteins across the aqueous intermembrane space, while the inner membrane complex mediates insertion of the precursor into the inner membrane.
A mutation in DDP1, the mammalian homolog of Tim8, leads to an X-linked disease (Mohr-Tranebjaerg syndrome) in which males have progressive deafness, blindness, and dystonia 10. This is the first disease caused by a defect in protein import, presumably because some key inner membrane proteins are present in decreased amounts. Because the spectrum of mitochondrial diseases varies, an interesting question is why this disease primarily affects the nervous system in contrast to other mitochondrial diseases affecting both nervous and muscular systems.
20. Roesch, K., S. P. Curran, L. Tranebjaerg, and C. M. Koehler. 2002. Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex. Hum. Mol. Genet. 11:477-486.
21. Curran, S. P., D. Leuenberger, W. Oppliger, and C. M. Koehler. 2002. The Tim9p-Tim10p complex binds to the transmembrane domains of the ADP/ATP carrier. EMBO J. 21:942-953.
22. Curran, S. P., D. Leuenberger, E. Schmidt, and C. M. Koehler. 2002. The role of the Tim8p-Tim13p complex in a conserved import pathway for mitochondrial polytopic inner membrane proteins. J. Cell Biol. 158:1017-1027.