Humanin

A micropeptide encoded by mitochondrial DNA and showing cytoprotective effects

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MT-RNR2

| Available structures

PDB| Human UniProt search: PDBe RCSB
| List of PDB id codes

1Y32, 2GD3, 5GIW

Identifiers
Aliases| RNR2, mitochondrially encoded 16S RNA, MTRNR2
External IDs| OMIM: 561010; MGI: 102492; GeneCards: RNR2; OMA:RNR2 - orthologs
| Gene ontology

Molecular function|

* signaling receptor binding
* protein binding
* receptor antagonist activity

Cellular component|

* cytoplasm
* perinuclear region of cytoplasm
* extracellular region
* mitochondrion

Biological process|

* negative regulation of apoptotic process
* leukocyte chemotaxis
* cellular iron ion homeostasis
* apoptotic process
* extracellular negative regulation of signal transduction
* G protein-coupled receptor signaling pathway
* negative regulation of execution phase of apoptosis
* negative regulation of signaling receptor activity

Sources:Amigo / QuickGO
| Orthologs

Species| Human| Mouse
Entrez| |

4550

17725

Ensembl| |

ENSG00000210082

ENSMUSG00000064339

UniProt| |

Q8IVG9

n/a

RefSeq (mRNA)| |

n/a

n/a

RefSeq (protein)| |

n/a

n/a

Location (UCSC)| n/a| n/a
PubMed search| [1]| [2]
Wikidata
| View/Edit Human| View/Edit Mouse

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The humanin gene is found within the 16S rRNA gene (MT-RNR2) in the mitochondrial genome

Humanin is a micropeptide encoded in the mitochondrial genome by the 16S ribosomal RNA gene, MT-RNR2. Its structure contains a three-turn α-helix, and no symmetry.

In in vitro and animal models, it appears to have cytoprotective effects.[3][4][5][6]

## Gene

[edit]

Humanin is encoded in the mitochondrial genome by the 16S ribosomal RNA gene, MT-RNR2.[7] Multiple paralogs are found in the nuclear genome (due to nuclear mitochondrial DNA segments) and are named MTRNR2L followed by a number. It is not entirely sure whether these paralogous isoforms are completely unexpressed.[8]

## Protein

[edit]

The expressed peptide[9] contains a three-turn α-helix, and has no symmetry.[9]

The length of the peptide depends on where it is produced. If it is produced inside the mitochondria it will be 21 amino acids long.[10] If it is produced outside the mitochondria, in the cytosol, it will be 24 amino acids long.[10] Both peptides have been shown to have biological activity.[10][11]

## Other species

[edit]

Humanin is the most well-conserved of the mitochondria-derived peptides, found in such diverse species as humans, naked mole rats, and nematodes.[5] Overexpression of humanin in Caenorhabditis elegans has been shown to extend the lifespan of that nematode by increasing autophagy.[5]

The rat, Rattus norvegicus, has a gene, rattin (C0HLU6, "Humanin-like protein"), that encodes a 38 amino acid peptide homologous to humanin.[12] The two genes produce cDNAs that show 88% sequence identity.[12] The peptides are 81% identical, with the carboxyl terminal sequence in rattin being 14 amino acids longer than in humanin.[12] Of the 24 amino acids in the rest of the rat sequence, 20 are identical to the amino acids in the human sequence.[12]

The mouse MT-RNR2 humanin ortholog is a pseudogene, so no humanin is produced from the mtDNA. However, the nuclear genome harbors (like in humans) many copies of mitochondrial genomes, and one copy of the humanin homolog, Gm20594 (J3QJY3), is actively expressed.[13]

## Function

[edit]

This section needs expansion. You can help by adding to it. (August 2017)

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Humanin has several cytoprotective effects.[14]

## Interactions

[edit]

Extracellular interaction with a tripartite receptor composed of gp130, WSX1, and CNTFR, as well as interaction with the formyl peptide receptor 2 (formylpeptide-like-1 receptor) have been published.[15][16]

Intracellular interaction with BAX, tBID, IGFBP3, and TRIM11 may also be required for the effects of humanin.[11][17][18][19]

## Discovery

[edit]

Humanin was the first mitochondria-derived peptide to be discovered.[5] Humanin was independently found by three different labs looking at different parameters. The first to publish, in 2001, was the Nishimoto lab, which found humanin while looking for possible proteins that could protect cells from amyloid beta, a major component of Alzheimer's disease.[7] The Reed lab found humanin when screening for proteins that could interact with Bcl-2-associated X protein (Bax), a major protein involved in apoptosis.[11] The Pinchas Cohen lab independently discovered humanin when screening for proteins that interact with IGFBP3.[17]

## Research

[edit]

Experiments using cultured cells have demonstrated that humanin has both neuroprotective as well as cytoprotective effects and experiments in rodents have found that it has protective effects in Alzheimer's disease models, Huntington's disease models and stroke models.[20]

Humanin is proposed to have myriad neuroprotective and cytoprotective effects. Both studies in cells and rodents have both found that administration of humanin or humanin derivatives increases survival and/or physiological parameters in Alzheimer's disease models.[21][22] In addition to Alzheimer's disease, humanin has other neuroprotective effects against models of Huntington's disease, prion disease, and stroke.[23][24][25]

Beyond the possible neuroprotective effects, humanin protects against oxidative stress, atherosclerotic plaque formation, and heart attack.[26][27][28][29] Humanin activates chaperone-mediated autophagy in a dose-dependent manner.[3] Humanin decreases production of inflammatory cytokines, which is part of its anti-apoptotic effect.[4] Metabolic effects have also been demonstrated and humanin helps improve survival of pancreatic beta-cells, which may help with type 1 diabetes,[30] and increases insulin sensitivity, which may help with type 2 diabetes.[31][6] In rats, the humanin analog appears to normalize glucose levels and reduce diabetes symptoms.[32]

Rattin shows the same ability as humanin to defend neurons from the toxicity of beta-amyloid, associated with the degeneration in Alzheimer's disease.[12]

Small humanin-like peptides are a group of peptides found in the mitochondrial 16S rRNA, and also possess retrograde signaling functions.

## References

[edit]

1. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
2. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. ^ a b Cai H, Liu Y, Men H, Zheng Y (2021). "Protective Mechanism of Humanin Against Oxidative Stress in Aging-Related Cardiovascular Diseases". Frontiers in Endocrinology. 12: 683151. doi:10.3389/fendo.2021.683151. PMC 8222669. PMID 34177809.
4. ^ a b Conte M, Martucci M, Franceschi C, Salvioli S (2020). "Mitochondria, immunosenescence and inflammaging: a role for mitokines?". Seminars in Immunopathology. 42 (5): 607–617\. doi:10.1007/s00281-020-00813-0. PMC 7666292. PMID 32757036.
5. ^ a b c d Miller B, Kim S, Cohen P (2022). "Mitochondria-derived peptides in aging and healthspan". Journal of Clinical Investigation. 132 (9): e158449. doi:10.1172/JCI158449. PMC 9057581. PMID 35499074.
6. ^ a b Burtscher J, Soltany A, Khamoui AV (2023). "Mitochondrial stress and mitokines in aging". Aging Cell. 22 (2): e13770. doi:10.1111/acel.13770. PMC 9924952. PMID 36642986.
7. ^ a b Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, Sobue G, Koide T, Tsuji S, Lang J, Kurokawa K, Nishimoto I (May 2001). "A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta". Proceedings of the National Academy of Sciences of the United States of America. 98 (11): 6336–41\. Bibcode:2001PNAS...98.6336H. doi:10.1073/pnas.101133498. PMC 33469. PMID 11371646.
8. ^ Bodzioch M, Lapicka-Bodzioch K, Zapala B, Kamysz W, Kiec-Wilk B, Dembinska-Kiec A (October 2009). "Evidence for potential functionality of nuclearly-encoded humanin isoforms". Genomics. 94 (4): 247–56\. doi:10.1016/j.ygeno.2009.05.006. PMID 19477263.
9. ^ a b Benaki D, Zikos C, Evangelou A, Livaniou E, Vlassi M, Mikros E, Pelecanou M (April 2005). "Solution structure of humanin, a peptide against Alzheimer's disease-related neurotoxicity". Biochemical and Biophysical Research Communications. 329 (1): 152–60\. doi:10.1016/j.bbrc.2005.01.100. PMID 15721287. Archived from the original on 2015-02-08. Retrieved 2014-07-07.
10. ^ a b c Yen K, Lee C, Mehta H, Cohen P (February 2013) [2013]. "The emerging role of the mitochondrial-derived peptide humanin in stress resistance". Journal of Molecular Endocrinology. 50 (1) (published Feb 2013): R11-9. doi:10.1530/JME-12-0203. PMC 3705736. PMID 23239898.
11. ^ a b c Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, Reed JC (May 2003). "Humanin peptide suppresses apoptosis by interfering with Bax activation". Nature. 423 (6938): 456–61\. Bibcode:2003Natur.423..456G. doi:10.1038/nature01627. PMID 12732850. S2CID 4423176.
12. ^ a b c d e Caricasole A, Bruno V, Cappuccio I, Melchiorri D, Copani A, Nicoletti F (August 2002) [2002]. "A novel rat gene encoding a Humanin-like peptide endowed with broad neuroprotective activity". FASEB Journal. 16 (10): 1331–3\. doi:10.1096/fj.02-0018fje. PMID 12154011. S2CID 31415552.
13. ^ Kim, J; Choi, JW; Namkung, J (31 January 2021). "Expression Profile of Mouse Gm20594, Nuclear-Encoded Humanin-Like Gene". Journal of Lifestyle Medicine. 11 (1): 13–22\. doi:10.15280/jlm.2021.11.1.13. PMC 7957044. PMID 33763338.
14. ^ Kim SJ, Xiao J, Wan J, Cohen P, Yen K (November 2017). "Mitochondrially derived peptides as novel regulators of metabolism". The Journal of Physiology. 595 (21): 6613–6621\. doi:10.1113/JP274472. PMC 5663826. PMID 28574175.
15. ^ Hashimoto Y, Kurita M, Aiso S, Nishimoto I, Matsuoka M (June 2009). "Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130". Molecular Biology of the Cell. 20 (12): 2864–73\. doi:10.1091/mbc.E09-02-0168. PMC 2695794. PMID 19386761.
16. ^ Ying G, Iribarren P, Zhou Y, Gong W, Zhang N, Yu ZX, Le Y, Cui Y, Wang JM (June 2004). "Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor". Journal of Immunology. 172 (11): 7078–85\. doi:10.4049/jimmunol.172.11.7078. PMID 15153530.
17. ^ a b Ikonen M, Liu B, Hashimoto Y, Ma L, Lee KW, Niikura T, Nishimoto I, Cohen P (October 2003). "Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis". Proceedings of the National Academy of Sciences of the United States of America. 100 (22): 13042–7\. Bibcode:2003PNAS..10013042I. doi:10.1073/pnas.2135111100. PMC 240741. PMID 14561895.
18. ^ Zhai D, Luciano F, Zhu X, Guo B, Satterthwait AC, Reed JC (April 2005). "Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak". The Journal of Biological Chemistry. 280 (16): 15815–24\. doi:10.1074/jbc.M411902200. PMID 15661737.
19. ^ Niikura T, Hashimoto Y, Tajima H, Ishizaka M, Yamagishi Y, Kawasumi M, Nawa M, Terashita K, Aiso S, Nishimoto I (March 2003). "A tripartite motif protein TRIM11 binds and destabilizes Humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults". The European Journal of Neuroscience. 17 (6): 1150–8\. doi:10.1046/j.1460-9568.2003.02553.x. PMID 12670303. S2CID 1345339.
20. ^ Yen K, Lee C, Mehta H, Cohen P (February 2013). "The emerging role of the mitochondrial-derived peptide humanin in stress resistance". Journal of Molecular Endocrinology. 50 (1): R11-9. doi:10.1530/JME-12-0203. PMC 3705736. PMID 23239898.
21. ^ Tajima H, Kawasumi M, Chiba T, Yamada M, Yamashita K, Nawa M, Kita Y, Kouyama K, Aiso S, Matsuoka M, Niikura T, Nishimoto I (March 2005). "A humanin derivative, S14G-HN, prevents amyloid-beta-induced memory impairment in mice". Journal of Neuroscience Research. 79 (5): 714–23\. doi:10.1002/jnr.20391. PMID 15678515. S2CID 25194143.
22. ^ Hashimoto Y, Niikura T, Ito Y, Sudo H, Hata M, Arakawa E, Abe Y, Kita Y, Nishimoto I (December 2001). "Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults". The Journal of Neuroscience. 21 (23): 9235–45\. doi:10.1523/JNEUROSCI.21-23-09235.2001. PMC 6763898. PMID 11717357.
23. ^ Kariya S, Hirano M, Nagai Y, Furiya Y, Fujikake N, Toda T, Ueno S (2005). "Humanin attenuates apoptosis induced by DRPLA proteins with expanded polyglutamine stretches". Journal of Molecular Neuroscience. 25 (2): 165–9\. doi:10.1385/JMN:25:2:165. PMID 15784964. S2CID 23766205.
24. ^ Sponne I, Fifre A, Koziel V, Kriem B, Oster T, Pillot T (January 2004). "Humanin rescues cortical neurons from prion-peptide-induced apoptosis". Molecular and Cellular Neurosciences. 25 (1): 95–102\. doi:10.1016/j.mcn.2003.09.017. PMID 14962743. S2CID 20276062.
25. ^ Xu X, Chua CC, Gao J, Hamdy RC, Chua BH (October 2006). "Humanin is a novel neuroprotective agent against stroke". Stroke. 37 (10): 2613–9\. doi:10.1161/01.STR.0000242772.94277.1f. PMID 16960089.
26. ^ Bachar AR, Scheffer L, Schroeder AS, Nakamura HK, Cobb LJ, Oh YK, Lerman LO, Pagano RE, Cohen P, Lerman A (November 2010). "Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress". Cardiovascular Research. 88 (2): 360–6\. doi:10.1093/cvr/cvq191. PMC 2952532. PMID 20562421.
27. ^ Oh YK, Bachar AR, Zacharias DG, Kim SG, Wan J, Cobb LJ, Lerman LO, Cohen P, Lerman A (November 2011). "Humanin preserves endothelial function and prevents atherosclerotic plaque progression in hypercholesterolemic ApoE deficient mice". Atherosclerosis. 219 (1): 65–73\. doi:10.1016/j.atherosclerosis.2011.06.038. PMC 3885346. PMID 21763658.
28. ^ Zacharias DG, Kim SG, Massat AE, Bachar AR, Oh YK, Herrmann J, Rodriguez-Porcel M, Cohen P, Lerman LO, Lerman A (2012). Westermark P (ed.). "Humanin, a cytoprotective peptide, is expressed in carotid atherosclerotic [corrected] plaques in humans". PLOS ONE. 7 (2): e31065. Bibcode:2012PLoSO...731065Z. doi:10.1371/journal.pone.0031065. PMC 3273477. PMID 22328926.
29. ^ Muzumdar RH, Huffman DM, Calvert JW, Jha S, Weinberg Y, Cui L, Nemkal A, Atzmon G, Klein L, Gundewar S, Ji SY, Lavu M, Predmore BL, Lefer DJ (October 2010). "Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice". Arteriosclerosis, Thrombosis, and Vascular Biology. 30 (10): 1940–8\. doi:10.1161/ATVBAHA.110.205997. PMC 2941397. PMID 20651283.
30. ^ Hoang PT, Park P, Cobb LJ, Paharkova-Vatchkova V, Hakimi M, Cohen P, Lee KW (March 2010). "The neurosurvival factor Humanin inhibits beta-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice". Metabolism. 59 (3): 343–9\. doi:10.1016/j.metabol.2009.08.001. PMC 2932671. PMID 19800083.
31. ^ Muzumdar RH, Huffman DM, Atzmon G, Buettner C, Cobb LJ, Fishman S, Budagov T, Cui L, Einstein FH, Poduval A, Hwang D, Barzilai N, Cohen P (July 2009). Vella A (ed.). "Humanin: a novel central regulator of peripheral insulin action". PLOS ONE. 4 (7): e6334. Bibcode:2009PLoSO...4.6334M. doi:10.1371/journal.pone.0006334. PMC 2709436. PMID 19623253.
32. ^ Hall, Stephen S. (March 2012). "New Clues to a Long Life". National Geographic. Archived from the original on 30 August 2017. Retrieved 30 August 2017.