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


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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    • "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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    ABSTRACT: Mitochondrial dysfunction and alterations in energy metabolism have been implicated in a variety of human diseases. Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. Here, we provide a link between PHB2 deficiency and hyperactive insulin/IGF-1 signaling. Deletion of PHB2 in podocytes of mice, terminally differentiated cells at the kidney filtration barrier, caused progressive proteinuria, kidney failure, and death of the animals and resulted in hyperphosphorylation of S6 ribosomal protein (S6RP), a known mediator of the mTOR signaling pathway. Inhibition of the insulin/IGF-1 signaling system through genetic deletion of the insulin receptor alone or in combination with the IGF-1 receptor or treatment with rapamycin prevented hyperphosphorylation of S6RP without affecting the mitochondrial structural defect, alleviated renal disease, and delayed the onset of kidney failure in PHB2-deficient animals. Evidently, perturbation of insulin/IGF-1 receptor signaling contributes to tissue damage in mitochondrial disease, which may allow therapeutic intervention against a wide spectrum of diseases. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    EMBO Molecular Medicine 02/2015; 7(3). DOI:10.15252/emmm.201404916 · 8.67 Impact Factor
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    • "Interestingly, human recombinant SLP2 was demonstrated to bind preferentially to cardiolipin (CL) in an in vitro pull-down assay that utilized liposomes with varying phospholipid composition (Christie et al., 2011), although the specificity of this interaction is debatable because the assay lacked additional control proteins. Additionally, yeast genetic studies have revealed that enzymes involved in CL and phosphatidylethanolamine (PE) synthesis pathways are essential for survival in phb knockout strains, underlining a functional link between lipid synthesis and PHBs (Birner et al., 2003; Osman et al., 2009). "
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    ABSTRACT: The band-7 protein family comprises a diverse set of membrane-bound proteins characterized by the presence of a conserved domain. The exact function of this band-7 domain remains elusive, but examples from animal and bacterial stomatin-type proteins demonstrate binding to lipids and the ability to assemble into membrane-bound oligomers that form putative scaffolds. Some members, such as prohibitins (PHB) and human stomatin-like protein 2 (HsSLP2), localize to the mitochondrial inner membrane where they function in cristae formation and hyperfusion. In Arabidopsis, the band-7 protein family has diversified and includes plant-specific members. Mitochondrial-localized members include prohibitins (AtPHBs) and two stomatin-like proteins (AtSLP1 and -2). Studies into PHB function in plants have demonstrated an involvement in root meristem proliferation and putative scaffold formation for mAAA proteases, but it remains unknown how these roles are achieved at the molecular level. In this minireview we summarize the current status of band-7 protein functions in Arabidopsis, and speculate how the mitochondrial members might recruit specific lipids to form microdomains that could shape the organization and functioning of the respiratory chain.
    Frontiers in Plant Science 04/2014; 5:141. DOI:10.3389/fpls.2014.00141 · 3.95 Impact Factor
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    • "It is tempting to speculate that, like Ups1p and PA (Connerth et al., 2012), either of these proteins can transport CL (or MLCL) between the IM and OM. Interestingly , total CL levels in UPS2 and UPS3 mutants remain largely unaffected (Osman et al., 2009; Tamura et al., 2009), but the relative distribution of CL between the IM and OM has never been analyzed. "
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    ABSTRACT: The signature mitochondrial phospholipid cardiolipin plays an important role in mitochondrial function, and alterations in cardiolipin metabolism are associated with human disease. Topologically, cardiolipin biosynthesis and remodeling is complex. Precursor phospholipids must be transported from the ER, across the mitochondrial outer membrane to the matrix-facing leaflet of the inner membrane, where cardiolipin biosynthesis commences. Post-synthesis, cardiolipin undergoes acyl chain remodeling, requiring additional trafficking steps, before it achieves its final distribution within both mitochondrial membranes. This process is regulated at several points via multiple independent mechanisms. Here, we review the regulation and topology of cardiolipin biosynthesis and remodeling in the yeast Saccharomyces cerevisiae. Although cardiolipin metabolism is more complicated in mammals, yeast have been an invaluable model for dissecting the steps required for this process.
    Chemistry and Physics of Lipids 10/2013; 179. DOI:10.1016/j.chemphyslip.2013.10.008 · 2.42 Impact Factor
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