title: The prohibitin family of mitochondrial proteins regulate replicative lifespan.
abstract: Cellular senescence is determined by multiple factors, including the genetic regulation of metabolism and responses to endogenous and exogenous stresses [1-4]. Recent studies implicate a limited number of gene products in elongating lifespan in yeast and Caenorhabditis elegans [2-4]; these include the C, elegans gene cik-1, a central regulator of metabolism [5], and yeast RAS2, which controls the response to ultraviolet irradiation and other stresses [3]. Another gene postulated to effect senescence is PHB1, the yeast homologue of prohibitin [3], a rodent gene initially identified as a potential regulator of growth arrest and tumour suppressor [6-8]. Highly conserved prohibitin homologues have been identified in mammals [9], Drosophila [10], C. elegans [9], plants [11] and yeast. A second mammalian gene, encoding BAP37, a protein with sequence similarity to prohibitin, is thought to be involved in lymphocyte function [9]. Here, we show that the nuclear-encoded mammalian prohibitin and BAP37 proteins are present in mitochondria, are co-expressed, and interact physically with each other. Deletion of the Saccharomyces cerevisiae homologues, PHB1 and PHB2, results in a decreased replicative lifespan and a defect in mitochondrial membrane potential. Our observations highlight the relationship between the metabolic efficiency of cells and the ageing process, and provide evidence for its evolutionary conservation.
authors.affiliation: Department of Molecular and Cellular Pathology, University of Dundee, Ninewells Hospital and Medical School, UK. pjcoates@ninewells.dundee.ac.uk
authors.forename: P J
authors.initials: PJ
authors.lastname: Coates
authors.forename: D J
authors.initials: DJ
authors.lastname: Jamieson
authors.forename: K
authors.initials: K
authors.lastname: Smart
authors.forename: A R
authors.initials: AR
authors.lastname: Prescott
authors.forename: P A
authors.initials: PA
authors.lastname: Hall
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D029742:Caenorhabditis elegans Proteins; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D000091402:Prohibitins; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid
chemical_list: D029742:Caenorhabditis elegans Proteins; C000717328:PHB protein, human; C000717329:PHB1 protein, S cerevisiae; C000717331:PHB2 protein, human; C000717333:Phb2 protein, mouse; D000091402:Prohibitins; D011506:Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; C000717338:prohibitin 2, C elegans