Humanin: Functional Interfaces with IGF-I

Xiao, Jialin; Kim, S.-J.; Cohen, Pinchas; Yen, Kelvin

doi:10.1016/j.ghir.2016.03.005

Cited by 37 publications

(44 citation statements)

References 77 publications

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“…Humanin is secreted from cells and thus humanin is detected in both conditioned medium and plasma [7, 8]. The plasma levels of humanin decline with age in mice and humans [9] and their levels are positively correlated with longevity in mouse models [10]. The long-lived Ames dwarf mice have a 50% increase in circulating humanin levels, whereas the short-lived GH-transgenic mice have lower levels [11–13].…”

Section: Introductionmentioning

confidence: 99%

The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling differences in the hippocampus

et al. 2016

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Humanin is a small secreted peptide that is encoded in the mitochondrial genome. Humanin and its analogues have a protective role in multiple age-related diseases including type 2 diabetes and Alzheimer's disease, through cytoprotective and neuroprotective effects both in vitro and in vivo. However, the humanin-mediated signaling pathways are not well understood. In this paper, we demonstrate that humanin acts through the GP130/IL6ST receptor complex to activate AKT, ERK1/2, and STAT3 signaling pathways. Humanin treatment increases phosphorylation in AKT, ERK 1/2, and STAT3 where PI3K, MEK, and JAK are involved in the activation of those three signaling pathways, respectively. Furthermore, old mice, but not young mice, injected with humanin showed an increase in phosphorylation in AKT and ERK1/2 in the hippocampus. These findings uncover a key signaling pathway of humanin that is important for humanin's function and also demonstrates an age-specific in vivo effect in a region of the brain that is critical for memory formation in an age-dependent manner.

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Section: Introductionmentioning

confidence: 99%

The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling differences in the hippocampus

et al. 2016

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“…1). The characteristics of the variant amino acids revealed a functional pattern that was also noted in a previous studies [225,247]. The region between proline 3 to proline 19 was described as the "core domain" of humanin that is essential for the secretion of the full-length peptide from the cell despite the wide variability at position 3 between species.…”

Section: S-humanin and Sequence Homologysupporting

confidence: 69%

“…Residues 3-19 have also been described as the "core domain" of the peptide and are responsible for its neuroprotective activity [224]. Modification of core domain amino acids was found to yield analogues resulting in increased potency, affect binding to growth-factor binding proteins, as well as affect its own secretion [225].…”

Section: Introductionmentioning

confidence: 99%

“…In addition to its neuroprotective effects (also including improving memory and learning) [233][234][235], humanin has been proposed to have several cytoprotective effects, including protection against oxidative stress, atherosclerotic plaque formation, stimulating pancreatic beta-cell and insulin sensitivity, and suppressing apoptosis. Apoptotic effects have been well characterized [65,221,225,228,233,[235][236][237][238][239][240][241][242]; they include protection from Aβ-induced toxicity of cerebrovascular smooth muscle cells and by interacting with insulin-like growth factorbinding protein 3 (IGFBP3) where humanin blocks IGFBP3-induced apoptosis in glial cell lines [231].…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Antioxidant Defenses, DNA Damage Repair, the Immune Response, and Neuroprotection During Hibernation in the Thirteen-Lined Ground Squirrel

Szereszewski¹

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Hibernation is a fascinating survival adaptation that allows animals to transition into a torpid state to survive the winter by coordinating a strong suppression of metabolic rate, conservation of fuel/energy, and reduction of body temperature. This strategy permits thirteen-lined ground squirrels (Ictidomys tridecemlineatus) and other hibernating mammals to endure the harsh winter season when there is little access to food. Many energy-expensive cellular processes are suppressed, including gene transcription and protein synthesis/turnover, but are reactivated rapidly when animals arouse back to euthermia. Both torpor and arousal can have damaging consequences; for example, during arousal, reactive oxygen species flood the cell causing oxidative damage to numerous cellular components. Therefore, hibernation requires many pro-survival mechanisms to mitigate multiple types of damage: e.g. from oxidative damage, DNA damage, and pathogen attack, among others. The research reported in this thesis on damage control processes in hibernators shows that antioxidant enzymes such as PRDXs are upregulated in key tissues but in an isoform-specific and time-specific manner over the torpor-arousal cycle. PRDX2, 3, 4 and 6 were found to be significantly upregulated in specific tissues.Similarly, DNA damage repair is initiated during torpor and is characterized by the binding of repair proteins such as Ku80 and the MRN complex to the site of breaks, but ligation (with XLF) reactions to fully repair DNA do not appear to occur until the arousal period.Pro-inflammatory mechanisms are also used to deal with pathogens; these remain active at basal levels in a tissue-specific manner during torpor, but are up-regulated in the final stages just before arousal or only during arousal depending on the tissue, such as the induction of CCL5, a recruiter of monocytes. A cyto/neuro-protective mitochondrial peptide, shumanin, was also identified that is induced in a tissue-specific manner, helping to protect key organs such as the brain cortex and adipose tissues. The results show that hibernation is a complex, multi-faceted process that employs specific adaptations of damage prevention/repair pathways to protect squirrel tissues from damage not only during prolonged torpor but over the transitional states to/from torpor and does so expertly while conserving energy until such a time that repair mechanisms may be fully initiated.iv

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“…Recent studies showed that in addition to the above mentioned 37 genes, the mitochondrial chromosome also encodes multiple biologically active peptides derived from small open reading frames (ORF) 15–19 . We discovered one such mitochondrial derived peptide (MDP) encoded from the 12S rRNA in the mtDNA called m itochondrial o pen-reading-frame of the twelve S rRNA – c (MOTS-c) 20 .…”

Section: Introductionmentioning

confidence: 99%

A Pro-Diabetogenic mtDNA Polymorphism in the Mitochondrial-Derived Peptide, MOTS-c

Zempo

Kim

Fuku

et al. 2019

Preprint

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49Type 2 Diabetes (T2D) is an emerging public health problem in Asia. An Asian mitochondrial DNA 50 variation m.1382A>C (rs111033358) leads to a K14Q amino acid replacement in MOTS-c, an 51 insulin sensitizing mitochondrial-derived peptide. Meta-analysis of three cohorts (n=27,527, J-52 MICC, MEC, and TMM) showed that males but not females with the C-allele exhibit a higher 53 prevalence of T2D. Furthermore, in J-MICC, only males with the C-allele in the lowest tertile of 54 physical activity increased their prevalence of T2D, demonstrating a kinesio-genomic interaction. 55High-fat fed, male mice injected with MOTS-c showed reduced weight and improved glucose 56 tolerance, but not K14Q-MOTS-c treated mice. Like the human data, female mice were unaffected. 57Mechanistically, K14Q-MOTS-c leads to diminished insulin-sensitization in vitro. Thus, the 58 m.1382A>C polymorphism is associated with susceptibility to T2D in men, possibly interacting with 59 exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c. 60 61 64 65The prevalence of type 2 diabetes mellitus (T2D) is growing dramatically. Over 400 million 66 individuals were diagnosed with T2D worldwide in 2015, and the International Diabetes Federation 67 projects that at least 600 million people will need to be treated for T2D by 2040 1 . However, treating 68 T2D is challenging because the disease etiology is genetically heterogeneous and varies among 69 ethnicities 2-4 . For example, a recent meta-analysis showed that T2D is 72% heritable (95% CI: 61-70 78%) 2 , and the Western Pacific Region -including China and Japan -makes up ~37% of the total 71 T2D diagnoses in the world 1 . This is particularly noteworthy because although East-Asian 72 populations have lower mean body mass index (BMI) than Caucasian populations, they have a 73 higher susceptibility to T2D compared to Caucasians 5 . Furthermore, when matched for BMI, East 74Asians have a greater percentage of body fat and a tendency for increased visceral adiposity 6 . 75T2D in Asian patients is characterized by early beta cell dysfunction, in contrast to Caucasian 76 populations that have more insulin resistance 7,8 . Thus, ethnicity-based DNA variations likely 77 influence the pathogenesis of T2D. 78While diabetes directly caused by mutations in mtDNA are extremely rare 9 , several genetic 79 analyses revealed that mtDNA polymorphisms contribute to T2D risk in both European and Asian 80 populations 10,11 . Notably, mtDNA sequences are more varied by ethnicity compared to nuclear 81 DNA sequences due to the 10-times higher mutation rate of mtDNA compared to nuclear DNA 82 12,13 . As a result, certain mtDNA polymorphisms could contribute to the T2D prevalence in different 83 ethnicities. The human mitochondrial genome consists of 16,569-base pairs and encodes 37 84 genes including 13 full size proteins involved in oxidative phosphorylation, 2 rRNA, and 22 tRNA 85 genes that are necessary for protein synthesis within the mitochondria. Genetic polymorphisms in 86 t...

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Humanin: Functional Interfaces with IGF-I

Cited by 37 publications

References 77 publications

The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling differences in the hippocampus

The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling differences in the hippocampus

Regulation of Antioxidant Defenses, DNA Damage Repair, the Immune Response, and Neuroprotection During Hibernation in the Thirteen-Lined Ground Squirrel

A Pro-Diabetogenic mtDNA Polymorphism in the Mitochondrial-Derived Peptide, MOTS-c

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