Humanin is a micropeptide encoded in the mitochondrial genome by the

16S ribosomal RNA 16 S ribosomal RNA (or 16 S rRNA) is the RNA component of the 30S subunit of a prokaryotic ribosome ( SSU rRNA). It binds to the Shine-Dalgarno sequence and provides most of the SSU structure. The genes coding for it are referred to as 16S rR ...

gene,

MT-RNR2 Mitochondrially encoded 16S RNA (often abbreviated as ''16S'') is the mitochondrial large subunit ribosomal RNA that in humans is encoded by the MT-RNR2 gene. The MT-RNR2 gene also encodes the Humanin polypeptide that has been the target of Al ...

. Its structure contains a three-turn

α-helix The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ...

, and no symmetry. In ''in vitro'' and animal models, it appears to have cytoprotective effects.

Gene

Humanin is encoded in the mitochondrial genome by the

gene,

. Multiple isoforms are found in the nuclear genome and are named MTRNR2L followed by a number.

Protein

The expressed peptide contains a three-turn

, and has no symmetry. 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. If it is produced outside the mitochondria, in the cytosol, it will be 24 amino acids long. Both peptides have been shown to have biological activity.

Other species

The rat, ''Rattus norvegicus'', has a gene, ''rattin'', that encodes a 38 amino acid peptide homologous to humanin. The two genes produce

cDNA In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA (e.g., messenger RNA (mRNA) or microRNA (miRNA)) template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to express a sp ...

s that show 88% sequence identity. The peptides are 81% identical, with the carboxyl terminal sequence in rattin being 14 amino acids longer then in humanin. Of the 24 amino acids in the rest of the rat sequence, 20 are identical to the amino acids in the human sequence.

Function

Humanin has several cytoprotective effects.

Interactions

Extracellular interaction with a tripartite receptor composed of

gp130 Glycoprotein 130 (also known as gp130, IL6ST, IL6R-beta or CD130) is a transmembrane protein which is the founding member of the class of all cytokine receptors. It forms one subunit of the type I cytokine receptor within the IL-6 receptor famil ...

, WSX1, and CNTFR, as well as interaction with the formyl peptide receptor 2 (formylpeptide-like-1 receptor) have been published. Intracellular interaction with BAX, tBID, IGFBP3, and

TRIM11 Tripartite motif-containing protein 11 is a protein found in humans that is encoded by the ''TRIM11'' gene. The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, ...

may also be required for the effects of humanin.

Discovery

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 Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...

, a major component of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

. The Reed lab found humanin when screening for proteins that could interact with

Bcl-2-associated X protein Apoptosis regulator BAX, also known as bcl-2-like protein 4, is a protein that in humans is encoded by the ''BAX'' gene. ''BAX'' is a member of the Bcl-2 gene family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apopto ...

(Bax), a major protein involved in

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

. The

Pinchas Cohen Pinchas Cohen is the dean of the USC Leonard Davis School of Gerontology, holds the William and Sylvia Kugel Dean's Chair in Gerontology and serves as the executive director of the Ethel Percy Andrus Gerontology Center. Cohen graduated in 1986 wi ...

lab independently discovered humanin when screening for proteins that interact with

IGFBP3 Insulin-like growth factor-binding protein 3, also known as IGFBP-3, is a protein that in humans is encoded by the ''IGFBP3'' gene. IGFBP-3 is one of six IGF binding proteins ( IGFBP-1 to IGFBP-6) that have highly conserved structures and bind the ...

Research

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. 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

models. In addition to

, humanin has other neuroprotective effects against models of

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...

prion disease Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It i ...

, and

stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

. Beyond the possible neuroprotective effects, humanin protects against oxidative stress, atherosclerotic plaque formation, and heart attack. Metabolic effects have also been demonstrated and humanin helps improve survival of pancreatic beta-cells, which may help with

type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...

, and increases insulin sensitivity, which may help with

type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

. In rats, the humanin analog appears to normalize glucose levels and reduce diabetes symptoms. Rattin shows the same ability as humanin to defend neurons from the toxicity of

beta-amyloid Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which i ...

, the cause of degeneration in

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

References

{{reflist Peptides Alzheimer's disease Huntington's disease Stroke Neuroprotective agents