The cytochrome c import pathway differs markedly from the general route taken by the majority of other imported proteins, which is characterized by the import involvement of namely, surface receptors, the general insertion protein (GIP), contact sites and by the requirement of a membrane potential (delta psi). Unique features of both the cytochrome c precursor (apocytochrome c) and of the mechanism that transports it into mitochondria, have contributed to the evolution of a distinct import pathway that is not shared by any other mitochondrial protein analysed thus far. The cytochrome c pathway is particularly unique because i) apocytochrome c appears to have spontaneous membrane insertion-activity; ii) cytochrome c heme lyase seems to act as a specific binding site in lieu of a surface receptor and; iii) covalent heme addition and the associated refolding of the polypeptide appears to provide the free energy for the translocation of the cytochrome c polypeptide across the outer mitochondrial membrane.

Apoproteins↗

PubMedDate not supplied

Sensitivity to cyclosporin A is mediated by cyclophilin in Neurospora crassa and Saccharomyces cerevisiae.

Cyclosporin A, a cyclic fungal undecapeptide produced by Tolypocladium inflatum, is a potent immunosuppressive drug originally isolated as an antifungal antibiotic. Cyclosporin A (CsA) is widely used in humans to prevent rejection of transplanted organs such as kidney, heart, bone marrow and liver. The biochemical basis of CsA action is not known: its primary cellular target has been suggested to be calmodulin, the prolactin receptor or cyclophilin, a CsA-binding protein originally isolated from the cytosol of bovine thymocytes. Cyclophilin has been shown to be a highly conserved protein present in all eukaryotic cells tested and to be identical to peptidyl-prolyl cis-trans isomerase, a novel type of enzyme that accelerates the slow refolding phase of certain proteins in vitro. We demonstrate that in the lower eukaryotes N. crassa and S. cerevisiae, cyclo philin mediates the cytotoxic CsA effect. In CsA-resistant mutants of both organisms, the cyclophilin protein is either lost completely or, if present, has lost its ability to bind CsA.

Carrier Proteins↗

PubMedDate not supplied

Protein import into mitochondria.

Most mitochondrial proteins are encoded by the nuclear genome and thus have to be imported into mitochondria from the cytosol. Protein translocation across and into the mitochondrial membranes is a multistep process facilitated by the coordinated action of at least four specialized translocation systems in the outer and inner membranes of mitochondria. The outer membrane contains one general translocase, the TOM complex, whereas three distinct translocases are located in the inner membrane, which facilitates translocation of different classes of preproteins. The TIM23 complex mediates import of matrix-targeted preproteins with N-terminal presequences, whereas hydrophobic preproteins with internal targeting signals are inserted into the inner membrane via the TIM22 complex. The OXA translocase mediates the insertion of preproteins from the matrix space into the inner membrane. This review focuses on the structural organization and function of the import machinery of the model organisms of Saccharomyces cerevisiae and Neurospora crassa. In addition, the molecular basis of a new human mitochondrial disorder is discussed, the Mohr-Tranebjaerg syndrome. This is the first known disease, which is caused by an impaired mitochondrial protein import machinery leading to progressive neurodegeneration.

Animals↗