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      Humanin rescues cultured rat cortical neurons from NMDA-induced toxicity through the alleviation of mitochondrial dysfunction

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          Abstract

          N-methyl-D-aspartate (NDMA) receptor-mediated excitotoxicity has been implicated in a variety of pathological situations such as Alzheimer’s disease (AD) and Parkinson’s disease. However, no effective treatments for the same have been developed so far. Humanin (HN) is a 24-amino acid peptide originally cloned from the brain of patients with AD and it prevents stress-induced cell death in many cells/tissues. In our previous study, HN was found to effectively rescue rat cortical neurons. It is still not clear whether HN protects the neurons through the attenuation of mitochondrial dysfunction. In this study, excitatory toxicity was induced by NMDA, which binds the NMDA receptor in primarily cultured rat cortical neurons. We found that NMDA (100 μmol/L) dramatically induced the decrease of cell viability and caused mitochondrial dysfunction. Pretreatment of the neurons with HN (1 μmol/L) led to significant increases of mitochondrial succinate dehydrogenase (SDH) activity and membrane potential. In addition, HN pretreatment significantly reduced the excessive production of both reactive oxygen species (ROS) and nitric oxide (NO). Thus, HN could attenuate the excitotoxicity caused by the overactivation of the NMDA receptor through the alleviation of mitochondrial dysfunction.

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          Most cited references 30

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          Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists.

          N-methyl-d-aspartate receptors (NMDARs) are located in neuronal cell membranes at synaptic and extrasynaptic locations, where they are believed to mediate distinct physiological and pathological processes. Activation of NMDARs requires glutamate and a coagonist whose nature and impact on NMDAR physiology remain elusive. We report that synaptic and extrasynaptic NMDARs are gated by different endogenous coagonists, d-serine and glycine, respectively. The regionalized availability of the coagonists matches the preferential affinity of synaptic NMDARs for d-serine and extrasynaptic NMDARs for glycine. Furthermore, glycine and d-serine inhibit NMDAR surface trafficking in a subunit-dependent manner, which is likely to influence NMDARs subcellular location. Taking advantage of this coagonist segregation, we demonstrate that long-term potentiation and NMDA-induced neurotoxicity rely on synaptic NMDARs only. Conversely, long-term depression requires both synaptic and extrasynaptic receptors. Our observations provide key insights into the operating mode of NMDARs, emphasizing functional distinctions between synaptic and extrasynaptic NMDARs in brain physiology. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Humanin peptide suppresses apoptosis by interfering with Bax activation.

            Bax (Bcl2-associated X protein) is an apoptosis-inducing protein that participates in cell death during normal development and in various diseases. Bax resides in an inactive state in the cytosol of many cells. In response to death stimuli, Bax protein undergoes conformational changes that expose membrane-targeting domains, resulting in its translocation to mitochondrial membranes, where Bax inserts and causes release of cytochrome c and other apoptogenic proteins. It is unknown what controls conversion of Bax from the inactive to active conformation. Here we show that Bax interacts with humanin (HN), an anti-apoptotic peptide of 24 amino acids encoded in mammalian genomes. HN prevents the translocation of Bax from cytosol to mitochondria. Conversely, reducing HN expression by small interfering RNAs sensitizes cells to Bax and increases Bax translocation to membranes. HN peptides also block Bax association with isolated mitochondria, and suppress cytochrome c release in vitro. Notably, the mitochondrial genome contains an identical open reading frame, and the mitochondrial version of HN can also bind and suppress Bax. We speculate therefore that HN arose from mitochondria and transferred to the nuclear genome, providing a mechanism for protecting these organelles from Bax.
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              Humanin: a harbinger of mitochondrial-derived peptides?

              Mitochondria have been largely considered as 'end-function' organelles, servicing the cell by producing energy and regulating cell death in response to complex signals. Being cellular entities with vital roles, mitochondria communicate back to the cell and actively engage in determining major cellular policies. These signals, collectively referred to as retrograde signals, are encoded in the nuclear genome or are secondary products of mitochondrial metabolism. Here, we discuss humanin, the first small peptide of a putative set of mitochondrial-derived peptides (MDPs), which exhibits strong cytoprotective actions against various stress and disease models. The study of humanin and other mitochondrial-derived retrograde signal peptides will aid in the identification of genes and peptides with therapeutic and diagnostic potential in treating human diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                18 April 2017
                : 11
                : 1243-1253
                Affiliations
                [1 ]Anatomy Department, Changzhi Medical College, Changzhi, Shanxi
                [2 ]Key Laboratory of Tissue Regeneration of Henan Province, Xinxiang Medical University, Xinxiang, Henan
                [3 ]Clinical Laboratory of Heji Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi
                [4 ]Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing
                [5 ]Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi
                [6 ]Department of Radiology, China-Japan Friendship Hospital, Beijing
                [7 ]Department of Radiology, First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
                [8 ]School of Medicine, University of California – San Diego, San Diego, CA, USA
                Author notes
                Correspondence: Guo-Lin Ma, Department of Radiology, China-Japan Friendship Hospital, No. 2 Yinghua Dongjie, Chaoyang District, Beijing, 100029, People’s Republic of China, Email maguolin1007@ 123456qq.com
                Ying-Hua Zhang, Key Laboratory of Tissue Regeneration of Henan Province, Xinxiang Medical University, East Jinsui Road, Xinxiang, Henan 453003, People’s Republic of China, Email 125642685@ 123456qq.com
                Article
                dddt-11-1243
                10.2147/DDDT.S133042
                5402890
                © 2017 Cui et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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