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The Emerging Role of the Mitochondrial-Derived Peptide Humanin in Stress Resistance

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The Emerging Role of the Mitochondrial-Derived Peptide Humanin in Stress Resistance K YEN and others Role of humanin in stress 50:1 R11–R19 Review resistance The emerging role of the mitochondrial-derived peptide humanin in stress resistance Correspondence Kelvin Yen, Changhan Lee, Hemal Mehta and Pinchas Cohen should be addressed to P Cohen USC Davis School of Gerontology, University of Southern California, Los Angeles, California 90089-0191, USA Email [email protected] Abstract The discovery of humanin, a novel, mitochondrial-derived peptide, has created a potentially Key Words new category of biologically active peptide. As more research unravels the endogenous role " Apoptosis of humanin as well as its potential pharmacological use, its role in stress resistance has " Cardiovascular become clearer. Humanin protects cells from oxidative stress, serum starvation, hypoxia, and " Diabetes (all) other insults in vitro and also improves cardiovascular disease as well as Alzheimer’s disease " Signal transduction in vivo. In this review, we discuss the emerging role of humanin in stress resistance and its Journal of Molecular proposed mechanism of action. Endocrinology (2013) 50, R11–R19 Journal of Molecular Endocrinology An overview of mitochondrial function mitochondria are also believed to be the largest generator of free radicals in the cell (reviewed in Balaban Mitochondria are generally considered the powerhouse et al. (2005)). Free radicals are the major source of of the cell as the majority of cellular ATP production oxidative stress within a cell and these free radicals can occurs there. It is within the mitochondria that the Krebs oxidize and damage proteins, lipids, and DNA. Besides cycle occurs, setting up an electrochemical gradient that the physiological role that certain free radicals play, will be used to produce ATP (Salway 1994). In addition increased oxidative stress has been associated with to its role in energy production and metabolism, mito- a number of different diseases, although a beneficial chondria play a major role in apoptosis, oxidative stress, effect of transient oxidative stress has been reported as and calcium sequestration/signaling. well (Ristow et al. 2009, Ristow & Zarse 2010). The central role that mitochondria play in apoptosis Mitochondria possess an elaborate system for facil- C has been enumerated on several occasions (reviewed itating the transport of Ca2 in and out of their inner in Wang (2001) and Kantari & Walczak (2011)). membrane, which plays an important role in cytoplasmic C Mitochondria play a critical role in the intrinsic Ca2 signaling, ATP production, and hormone metab- C apoptotic pathway that is triggered by cellular damage olism. Deregulation of the mitochondrial Ca2 homeo- of which some cells are dependent on the mitochondria stasis can trigger cell death and disrupt the function of C for apoptosis (type 2), while others are not (type 1) intra-mitochondrial enzymes. Mitochondrial Ca2 uptake (Kantari & Walczak 2011). Furthermore, many nucleus- and release differ from other membrane-bound organelles C C encoded mitochondrial proteins directly activate apop- in that Ca2 uptake is not dependent on ATP and Ca2 C C C tosis when they are released from the mitochondria release uses gated channels and Na or H /Ca2 into the cytosol or nucleus. In addition to apoptosis, exchangers (reviewed in Drago et al. (2011)). http://www.jme.endocrinology-journals.org Ñ 2013 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-12-0203 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 04:29:36AM via free access Review K YEN and others Role of humanin in stress 50:1 R12 resistance Communication from the cell to the mitochondria is Humanin also interacts with insulin-like growth well established, but how mitochondria signal to the cell factor-binding protein 3 (IGFBP3), where it can block is relatively less understood. In addition to the chemical IGFBP3-induced apoptosis in glial cell lines but not in C signaling via Ca2 and reactive oxygen species (ROS), in neuronal cell lines or primary neurons (Ikonen et al. 2003). simpler organisms like yeast, mitochondria communicate Although humanin can block the apoptotic effects of with the cell via the retrograde signaling (RTG) pathway. IGFBP3 in glial cells, unexpectedly, IGFBP3 and humanin In animal cells, many of the genes of the RTG pathway have a positive, synergistic effect on protecting neurons do not exist, suggesting that animal mitochondria have from amyloid-b-induced apoptosis (Ikonen et al. 2003). an alternative method for signaling the cell. Two recent The discovery of humanin is interesting for many papers suggest that the mitochondrial unfolded protein reasons. It is a small, secreted, 24 or 21 amino acid peptide, response (UPR) may be an alternative way that mito- depending on cytoplasmic or mitochondrial translation chondria signal to the cell. The first paper used respectively, with biological activity that does not have a Caenorhabditis elegans to demonstrate that tissue-specific signal peptide for secretion but may act as a signal peptide mitochondrial dysfunction lead to a life-increasing, itself (Yamagishi et al. 2003). More interesting is the fact endocrine response and that this increase was dependent that it is the first new peptide discovered within the on the mitochondrial UPR (Durieux et al. 2011). mitochondrial genome since its complete sequencing in Another paper showed that mitochondria undergoing 1981 (discussed in further detail below) (Anderson et al. temperature stress release degraded protein peptides 1981). The mitochondrial genome itself is extremely small that trigger mitochondrial UPR (Haynes et al. 2010). and compact (16 569 nucleotides in humans), with no Humanin, the topic of this review, is another peptide known introns and very few non-coding nucleotides that possibly acts as a mitochondrial autocrine, paracrine, between adjacent genes; traditionally, it has been known and endocrine signal. to code for only 2 rRNAs, 13 mRNAs, and 22 tRNAs. Humanin is an open reading frame (ORF) found within the 16s rRNA gene (Fig. 1). Like a Russian nesting doll, The discovery of humanin humanin is a gene within a gene within a genome of an Approximately 10 years ago, the Nishimoto Lab (Hashimoto organelle within a cell and may represent the first peptide et al. 2001b) discovered humanin (MTRNR2) while of a new class of mitochondrial-derived peptides (MDP). searching for survival factors in the unaffected brain section of an Alzheimer’s patient. Using a cDNA library, Journal of Molecular Endocrinology they searched for genes that could resist apoptosis induced Humanin action in stress by a mutant form of amyloid precursor protein (APP Alzheimer’s disease V642I), which is a gene that is mutated in one form of familial Alzheimer’s disease (AD). They further showed As mentioned earlier, humanin was discovered during a that humanin could protect against other familial AD search for neurosurvival factors in unaffected areas of an genes but could not protect against a Huntington’s disease AD patient’s brain. Thus, it is not surprising that the best- model or amyotrophic lateral sclerosis model (Hashimoto studied aspect of humanin biology is in its beneficial et al. 2001a,b). This suggested that humanin conferred effects in protecting against AD-related stress. These initial specific protection to AD models and did not merely studies were first performed in cell culture and then protect cells from all apoptotic events. followed by in vivo studies using both pharmacological Humanin (HN/MTRNR2) has also been cloned as a mimetics of AD as well as mutant APP. The most recent BAX partner that could suppress apoptosis caused by studies have now started using different transgenic models staurosporine, serum deprivation, or u.v. irradiation (Guo of AD to examine the potential use of humanin to et al. 2003). Using co-immunoprecipitation experiments, ameliorate AD. humanin specifically bound to BAX, tBID, and BimEL The earliest humanin study showed that it could (BCL2L11), but not other BCL2 family proteins such as protect cells from apoptosis induced by amyloid b (Ab)1–43 BCL2 and BCL-B (BCL2L10) (Luciano et al. 2005, Zhai et al. and a follow-up study went even further showing that 2005). Furthermore, the anti-apoptotic effect of humanin humanin could protect against other mutated genes that was specific to BAX-dependent apoptosis, as apoptosis by cause familial AD such as APP, presenilin 1, and presenilin a BAX-independent stimulus, such as the use of tumor 2 (Hashimoto et al. 2001a,b). Although other factors such necrosis factor, was not suppressed. as IGF1 and basic FGF could protect neurons from (Ab)1–43, http://www.jme.endocrinology-journals.org Ñ 2013 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-12-0203 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 04:29:36AM via free access Review K YEN and others Role of humanin in stress 50:1 R13 resistance (Tajima et al. 2005). Injecting Ab 25–35 into mice (i.c.v.) causes memory deficits within 3 weeks, which was ameliorated by HNG treatment (Tajima et al. 2005). Supporting the memory improvements seen with HNG administration, ex vivo experiments using hippocampal brain slices have also shown that HNG can prevent the inhibition of long-term potentiation caused by Ab 25–35 Humanin applied an hour before recording (Zhang et al. 2009). Examination of acetylcholine-producing cells in the brain by staining for choline acetyltransferase, an enzyme used in the synthesis of acetylcholine, showed that Ab 25–35 decreased the number of immunoreactive cells and 16s that HNG was able to ameliorate this decrease (Tajima et al. 2005). Further examination of the in vivo effects of humanin/HNG on Ab toxicity showed that HNG was able to reduce the inflammatory response caused by Ab 25–35 as demonstrated by a decrease in reactive Mitochondrial astrocytes, microglial activation, TNFa levels, and IL6 genome levels (Miao et al. 2008).
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