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

Institute for Genetics, Centre for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50674, Germany.
The Journal of Cell Biology (Impact Factor: 9.83). 03/2009; 184(4):583-96. DOI: 10.1083/jcb.200810189
Source: PubMed

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, prohibitin-deficient yeast cells are viable and exhibit a reduced replicative life span. Here, we define 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 lipid-specific but coordinated manner. Lipid profiling by mass spectrometry of GEP-deficient mitochondria reveals a critical role of cardiolipin and phosphatidylethanolamine for survival of prohibitin-deficient cells. We propose that prohibitins control inner membrane organization and integrity by acting as protein and lipid scaffolds.

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Available from: Phat Vinh Dip, Mar 11, 2014
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    • "This complex positively modulates mitochondrial respiration, mitochondrial genome, mitochondrial assembly and ROS generation [56,57]. An interesting study in yeast reveals that PHB complex controls mitochondrial inner membrane organization and integrity by acting as protein chaperones and lipid scaffolds [59]. In fact, PHBs knockdown may trigger cytochromec-cardiolipin complex dissociation and further cytochrome c release, increasing cellular susceptibility to apoptosis [57]. "
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    • "Like MICOS, prohibitins have been implicated in nucleoid function and have been found to interact with nucleoid components in animals [144]. In S. cerevisiae, ERMES and MICOS components were found to be genetically linked to the prohibitin ring complex, suggesting they collaborate in a network responsible for mitochondrial lipid metabolism [6,71,145]. Phb1 and Phb2 were also shown to be high copy suppressors of mdm10 and mdm12 mutations [145]. "
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    ABSTRACT: The ER-mitochondria organizing network (ERMIONE) in Saccharomyces cerevisiae is involved in maintaining mitochondrial morphology and lipid homeostasis. ERMES and MICOS are two scaffolding complexes of ERMIONE that contribute to these processes. ERMES is ancient but has been lost in several lineages including animals, plants, and SAR (stramenopiles, alveolates and rhizaria). On the other hand, MICOS is ancient and has remained present in all organisms bearing mitochondrial cristae. The ERMIONE precursor evolved in the α-proteobacterial ancestor of mitochondria which had the central subunit of MICOS, Mic60. The subsequent evolution of ERMIONE and its interactors in eukaryotes reflects the integrative co-evolution of mitochondria and their hosts and the adaptive paths that some lineages have followed in their specialization to certain environments. By approaching the ERMIONE from a perspective of comparative evolutionary cell biology, we hope to shed light on not only its evolutionary history, but also how ERMIONE components may function in organisms other than S. cerevisiae.
    No preview · Article · Jan 2016 · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
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    • "The mitochondrial prohibitin (PHB) protein complex comprises two subunits, PHB1 and PHB2, that assemble into a high molecular weight ring complex in the mitochondrial inner membrane (Back et al, 2002; Tatsuta et al, 2005; Merkwirth & Langer, 2009). PHB proteins have multiple functions, they modulate mitochondrial m-AAA protease activity (Steglich et al, 1999) and control lipid distribution in the mitochondrial inner membrane (Osman et al, 2009b), and they serve as membrane-bound chaperones for the assembly of mitochondrial-encoded proteins (Nijtmans et al, 2000) and recruit membrane proteins to a specific lipid environment (Osman et al, 2009a). Acting as a membrane scaffold, the PHB complex is involved in maintaining mitochondrial integrity , indispensable for cristae morphogenesis, and fusion of the organelles (Kasashima et al, 2008; Merkwirth et al, 2008). "
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