The genetic interactome of prohibitins: Coordinated control of cardiolipin and phosphatidylethanolamine by conserved regulators in mitochondria

Abstract

Prohibitin ring complexes in the mitochondrial inner membrane regulate cell proliferation as well as the dynamics and function of mitochondria. Although prohibitins are essential in higher eukaryotes, prohibitindefi cient yeast cells are viable and exhibit a reduced replicative life span. Here, we defi ne the genetic interactome of prohibitins in yeast using synthetic genetic arrays, and identify 35 genetic interactors of prohibitins (GEP genes) required for cell survival in the absence of prohibitins. Proteins encoded by these genes include members of a conserved protein family, Ups1 and Gep1, which affect the processing of the dynamin-like GTPase Mgm1 and thereby modulate cristae morphogenesis. We show that Ups1 and Gep1 regulate the levels of cardiolipin and phosphatidylethanolamine in mitochondria in a lipidspecifi c but coordinated manner. Lipid profi ling by mass spectrometry of GEP-defi cient mitochondria reveals a critical role of cardiolipin and phosphatidylethanolamine for survival of prohibitin-defi cient cells. We propose that prohibitins control inner membrane organization and integrity by acting as protein and lipid scaffolds. © 2009 Osman et al.