| Research Abstract |
Mitochondria are involved in several fundamental cellular processes in higher eukaryotes including oxidative phosphorylation, calcium-signaling, and apoptosis. They are extremely dynamic entities changing their size, shape, position or copy number in cells during cellular differentiation, development, or under pathologic conditions. The majority of mitochondrial proteins are encoded by nuclear DNA, synthesized in the cytosol, and imported post-translationally into the mitochondrial sub-compartments. We have made the following progress toward the aim of two sub-projects, which contributed much in understanding the mechanisms of mammalian mitochondrial biogenesis and morphology regulation on the molecular level.
Targeting and topogenesis of mitochondrial membrane proteins: We analyzed targeting and insertion pathway of mitochondrial membrane proteins with distinct localization and topology including the N-terminal signal anchored proteins and. Most importantly, these experiments revealed
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that (1) C-terminal tail-anchored proteins of the outer membrane are integrated into the membrane through a common pathway independent of the TOM components, and that (ii) mitochondrial outer membrane proteins with multiple transmembrane segments are integrated into the membrane through a novel pathway that requires both Tom70 and intermembrane space components, but not the other TOM components. Furthermore, we characterized Tom40 as a preprotein translocating channel, and newly identified the import components of mammalian mitochondria, Tom70, Tom5, Tom6 and Tom40b.
Regulation of mitochondrial morphology and apoptosis: Although mitochondrial dynamic morphological changes are considered crucial for cellular functions, the underlying mechanisms, mainly in mammals, are poorly understood. We are devoting our efforts to studies of three mammalian GTP-binding proteins that are implicated in mitochondrial membrane morphogenesis and obtained the following results. (i) Identification of two mammalian mitochodnrial outrmembrane GTPases, Mfn1 and Mfn2, essential for fusion reaction; (ii) Identification of a novel protein MIB that negatively regulates activity of Mfn proteins; (iii) First demonstration of the importance of processing of the innermembrane GTPase OPA1 for mitochondrial fusion, and identification of the processing enzyme; (iv) Analysis of the function of cytoplasmic GTPase Drpl during cell cycle progression; (v) Production of DRP1-knockout mice; (vi) Demonstration of the importance of processing for the release Apoptosis Inducing Factor (AIF) from the intermembrane space; (vii) Identification of mitochondrial inner membrane protein MICS1 required for mitochondrial cristae and structure regulation; and (viii) Demonstration of the importance of the inner membrane Leucine zipper-, EF-hand-containing protein LETM1 for maintenance of the respiratory complexes and inner membrane structure. Less
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