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      Prohibitin Ligands in Cell Death and Survival: Mode of Action and Therapeutic Potential

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          Abstract

          Prohibitins (PHBs) are scaffold proteins that modulate many signaling pathways controlling cell survival, metabolism, and inflammation. Several drugs that target PHBs have been identified and evaluated for various clinical applications. Preclinical and clinical studies indicate that these PHB ligands may be useful in oncology, cardiology, and neurology, as well as against obesity. This review covers the physiological role of PHBs in health and diseases and current developments concerning PHB ligands.

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          Highlights

          ► Prohibitins regulate cell survival, metabolism, and inflammation ► Prohibitins act as a hub for many signaling pathways ► Prohibitin ligands are examined in cancer, Parkinson’s disease, and obesity

          Abstract

          Prohibitins are scaffold proteins that modulate many signaling pathways, controlling cell survival, metabolism, and inflammation. Thuaud et al. review prohibitins in health and diseases, current developments of small molecules targeting prohibitins, and their therapeutic potential.

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          Most cited references166

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          Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria.

          Prohibitins comprise an evolutionarily conserved and ubiquitously expressed family of membrane proteins with poorly described functions. Large assemblies of PHB1 and PHB2 subunits are localized in the inner membrane of mitochondria, but various roles in other cellular compartments have also been proposed for both proteins. Here, we used conditional gene targeting of murine Phb2 to define cellular activities of prohibitins. Our experiments restrict the function of prohibitins to mitochondria and identify the processing of the dynamin-like GTPase OPA1, an essential component of the mitochondrial fusion machinery, as the central cellular process controlled by prohibitins. Deletion of Phb2 leads to the selective loss of long isoforms of OPA1. This results in an aberrant cristae morphogenesis and an impaired cellular proliferation and resistance toward apoptosis. Expression of a long OPA1 isoform in PHB2-deficient cells suppresses these defects, identifying impaired OPA1 processing as the primary cellular defect in the absence of prohibitins. Our results therefore assign an essential function for the formation of mitochondrial cristae to prohibitins and suggest a coupling of cell proliferation to mitochondrial morphogenesis.
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            Reversal of obesity by targeted ablation of adipose tissue.

            Obesity is an increasingly prevalent human condition in developed societies. Despite major progress in the understanding of the molecular mechanisms leading to obesity, no safe and effective treatment has yet been found. Here, we report an antiobesity therapy based on targeted induction of apoptosis in the vasculature of adipose tissue. We used in vivo phage display to isolate a peptide motif (sequence CKGGRAKDC) that homes to white fat vasculature. We show that the CKGGRAKDC peptide associates with prohibitin, a multifunctional membrane protein, and establish prohibitin as a vascular marker of adipose tissue. Targeting a proapoptotic peptide to prohibitin in the adipose vasculature caused ablation of white fat. Resorption of established white adipose tissue and normalization of metabolism resulted in rapid obesity reversal without detectable adverse effects. Because prohibitin is also expressed in blood vessels of human white fat, this work may lead to the development of targeted drugs for treatment of obese patients.
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              Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion

              The signal transducer and activator of transcription 3 (STAT3) contributes to cardioprotection by ischemic pre- and postconditioning. Mitochondria are central elements of cardioprotective signaling, most likely by delaying mitochondrial permeability transition pore (MPTP) opening, and STAT3 has recently been identified in mitochondria. We now characterized the mitochondrial localization of STAT3 and its impact on respiration and MPTP opening. STAT3 was mainly present in the matrix of subsarcolemmal and interfibrillar cardiomyocyte mitochondria. STAT1, but not STAT5 was also detected in mitochondria under physiological conditions. ADP-stimulated respiration was reduced in mitochondria from mice with a cardiomyocyte-specific deletion of STAT3 (STAT3-KO) versus wildtypes and in rat mitochondria treated with the STAT3 inhibitor Stattic (STAT3 inhibitory compound, 6-Nitrobenzo[b]thiophene 1,1-dioxide). Mitochondria from STAT3-KO mice and Stattic-treated rat mitochondria tolerated less calcium until MPTP opening occurred. STAT3 co-immunoprecipitated with cyclophilin D, the target of the cardioprotective agent and MPTP inhibitor cyclosporine A (CsA). However, CsA reduced infarct size to a similar extent in wildtype and STAT3-KO mice in vivo. Thus, STAT3 possibly contributes to cardioprotection by stimulation of respiration and inhibition of MPTP opening.
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                Author and article information

                Contributors
                Journal
                Chem Biol
                Chem. Biol
                Chemistry & Biology
                Elsevier Ltd.
                1074-5521
                1879-1301
                21 March 2013
                21 March 2013
                21 March 2013
                : 20
                : 3
                : 316-331
                Affiliations
                [1 ]Therapeutic Innovation Laboratory (UMR 7200), CNRS/Université de Strasbourg, Faculté de Pharmacie, 67401 Illkirch Cedex, France
                [2 ]Biotechnology and Cell Signaling Laboratory (UMR 7242), CNRS/Université de Strasbourg, ESBS, 67412 Illkirch Cedex, France
                Author notes
                []Corresponding author desaubry@ 123456unistra.fr
                Article
                S1074-5521(13)00047-1
                10.1016/j.chembiol.2013.02.006
                7111013
                23521790
                5adf2e60-2010-41d8-9fdc-640a5b0e9eee
                Copyright © 2013 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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                Biochemistry
                Biochemistry

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