The mechanisms which underlie the turnover of membrane proteins in the cell remain poorly understood. Various plasma membrane proteins are internalized in a ubiquitin-dependent manner and degraded in lysosomes and vacuoles (14). Proteolysis of membrane proteins of the endoplasmic reticulum requires their retrograde transport to the cytosol and proceeds via the cytoplasmic ubiquitin-proteasome pathway (5, 30). Another proteolytic system has emerged from studies on the turnover of mitochondrial inner membrane proteins. Proteolysis is mediated by membrane-embedded ATP-dependent AAA proteases, which comprise a conserved protein family with homologues in various organisms, including bacteria, plants, yeasts and humans (18,28,31).Two AAA proteases have been identified in the mitochondrial inner membrane of Saccharomyces cerevisiae (11,26,34,35). Both proteases are composed of homologous subunits and form high-molecular-mass complexes of approximately 1 MDa (3,20). Their catalytic sites, however, are exposed to opposite membrane surfaces: the m-AAA protease containing Yta10p (Afg3p) and Yta12p (Rca1p) acts on the matrix side, while the i-AAA protease containing Yme1p is active in the intermembrane space (3,20). In S. cerevisiae, AAA proteases fulfill crucial roles in mitochondrial biogenesis. Deletion of YME1 impairs the respiratory competence of the cells at high temperature and results in changes in the morphology of mitochondria (6, 34). Cells lacking Yta10p or Yta12p, on the other hand, lose respiratory competence and exhibit deficiencies in the assembly of the F 1 F 0 -ATP synthase and respiratory chain complexes in the inner membrane (11,27,32,35). The m-AAA protease controls the expression of the intron-containing mitochondrial genes COB and COX1, affecting the splicing of the respective pre-mRNAs (2). In addition, evidence is accumulating for posttranslational functions of the m-AAA protease during the biogenesis of the respiratory chain (2, 27). Mutations in a human homologue of Yta10p and Yta12p, paraplegin, have recently been reported to cause a hereditary form of spastic paraplegia, pointing to important functions of AAA proteases also in higher eukaryotes (7).Prohibitin was originally identified in mammalian cells for its decreased expression in tumor cells and for its ability to negatively regulate cell proliferation (21,25). Subsequent studies established that prohibitin belongs to a ubiquitous protein family in eukaryotes which is highly conserved from yeast to human (9). In eukaryotic cells there are two homologues which were initially found in association with the plasma membrane in B lymphocytes (33) but later localized to the inner membrane of mitochondria in various cell types (4,8,15). The S. cerevisiae prohibitin homologues Phb1p and Phb2p have been implicated in the regulation of the replicative life span of the cells (4,8). Moreover, the observation of a genetic interaction of PHB1 or PHB2 with mitochondrial inheritance components points to a role for the maintenance of mitochondrial morphology...
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