MITOCHONDRIAL MEMBRANE METABOLIC ROLE OF CYTOCHROME C

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Cytochrome c is the only protein component of th mitochondrial respiratory chain that is not an integral protein of the inner mitochondrial membrane, but rather can readily dissociate from the outer surface of the membrane into the intermembrane space. Even though a wealth of information is available concerning many aspects of its operation there still exists a fundamental lack of knowledge about the mechanics of its function under normal intracellular physiological conditions. Thus, the transfer of electrons between the reductase and oxidase segments of the repsiratory chain, the major but not the only function of cytochrom c, could take place with very little movement of the protein (solid state model) by two-dimensional diffusion along the outer surface of the inner mitochondiral membrane or by free diffusion in the intermembrane space. Which of these processes or combinations of processes occurs, will depend on ionic strength, ionic composition, the appropriate Donnan equiibria, the large electric field generated by fixed charges on the membrane (estimated at 18.4x106 volt/meter), the occurrence of oxidative phosphoration and the morphological changes of the mitochondrial inner membrane attending changes in state of activity. There forces may be geared to operating cytochrome c as an on-off switch effecting respiratory control. To describe its physiological function it is proposed to: (1) develop biosynthetic procedures for inserting cytochrome c carrying a variety of labels into strictly intact mitochondria and use such preparations to define intramitochondrial localization and mobility of cytochrome c under functional conditions; (2) study the covalent crosslinking of cytochrome c to artificial membranes, isolated enzyme systems and mitochondrial inner membranes, as controls to the concepts developed under Section 1, and examine the role of phospholipid in cytochrome c binding; (3) examine the kinetic control of succinate oxidase activity by cytochrome c in mirochondiral inner membrane preparations; (4) continue chemical modification studies to examine the electron transfer reactions with cytochrome c peroxidase and the b5 superfamily of electron transfer proteins. These and related studies are expected to define the precise mode of physiological regulation of cytochrome c, leading the way to possible approaches to its artificial control.