GeneralIs Humanin The First Mitochondria-Derived Peptide?

Energy production and controlling cell death in response to complicated signals have led mitochondria to be seen as ‘end-function’ organelles. Mitochondria are autonomous organelles inside a cell that relay information and formulate fundamental cellular policies. Generally referred to as retrograde signals, these signals are encoded in the nuclear genome or are secondary products of mitochondrial metabolism.

Humanin is the first short peptide in a hypothesized series of mitochondria-derived peptides. Here, we address its possible cytoprotective activities in several stress and illness animal models. The research of Humanin and other mitochondrial-derived retrograde signal peptides will assist in discovering genes and peptides with potential in the context of various disorders.

Humanin was first discovered as a 24 amino acid (aa) peptide encoded by a cDNA theorized to prevent neuronal cell death caused by presenilin mutations linked to familial Alzheimer’s disease and amyloid-protein.

Studies suggest the cysteine of the Humanin peptide at position 8 is essential for its anti-apoptotic action, as indicated by mutagenesis experiments. Apoptosis-inducing protein Bax (Bcl-2 associated X protein) has been speculated to interact with Humanin. Research suggests that Humanin may block Bax’s movement from the cytosol to the mitochondria. Suppressing cytochrome c release in vitro and inhibiting Bax interaction with isolated mitochondria are two additional hypothesized properties of Humanin peptides.

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Mitochondrial Biology and Function

Mitochondria are thought to have originated as an endosymbiotic relationship between eukaryotic host cells and -proteobacteria. Eukaryotic evolution was drastically altered when the organism used oxygen to generate energy and biosynthetic precursors in large quantities, a feat made possible by the mitochondria (proto-mitochondrion).

Due to their prokaryotic origin, mitochondria are also unusual among intracellular organelles because they possess their genome. The bulk of the original bacterial genes is considered to have been lost or transferred to the nucleus throughout time, leaving just 13 full-size protein-encoding genes required for oxidative phosphorylation. Scientists are only just starting to investigate the possible significance of this region of the genome in aging, cancer, diabetes, deafness, and neurodegeneration.

Energy generation, management of programmed cell death (apoptosis), biosynthetic precursor production, heme synthesis, Fe-S cluster creation, ion homeostasis, and ROS production are just a few of the many critical cellular processes the mitochondria carry. Mitochondria are recognized to play an essential role in defining cellular functions, but how they convey this information to the host cell is poorly understood despite their importance. An exciting new idea for controlling cellular activities and determining cell destiny relies on mitochondrial communication, and we’ll go through that here.

Mitochondrial Peptides

Retrograde signaling describes how mitochondria convey information to the rest of the cell. Ca2+, cytochrome C (Cyt C), and reactive oxygen species have all been recognized as classic mitochondrial messengers. Mitochondrial DNA RNAs, or MDP, are a newly discovered class of retrograde signals exclusive to mitochondria. Humanin and other MDPs are hypothesized to regulate cell survival and metabolism in several ways, both endocrinely and intracellularly.

Retrograde Signaling

For a long time, mitochondria were considered “end-function” organelles that respond to cellular signals by controlling processes like energy generation and cell death. Cellular homeostasis requires a persistent and dynamic data flow between the mitochondria and the nucleus to maintain stability. Retrograde signaling refers to the mitochondria-initiated communication events that signal and control different cellular features under normal, stress, and disease situations.

Few retrograde signaling substances and pathways have been investigated so far. Cytochrome C, reactive oxygen species (ROS), calcium, iron, nitrogen oxide, carbon monoxide, and carbon dioxide are all mentioned here. Intriguing research on C. elegans demonstrated non-canonical signals released from mitochondria in response to proteotoxic shocks.

Humanin Peptide and the Cellular Level

In vitro studies have purported that Humanin may function within and outside cells. Humanin has been theorized to prevent apoptosis by interacting with pro-apoptotic proteins inside a cell, including Bax and IGFBP-3. Findings imply that extracellular Humanin may control critical cellular processes like survival, metabolism, and inflammation via two types of cell surface receptors.

Is Humanin The First Mitochondria-Derived Peptide?

Humanin is an evolutionarily conserved polypeptide. In 2001, it was found by accident while screening a cDNA library made from an AD research model’s brain tissue that had survived the illness. Researchers discovered multiple clones with sequences identical to the mitochondrial 16S rRNA section. This discovery was realized through unbiased functional screening to protect neuronal cells from cell death induced by amyloid precursor protein (APP) mutants associated with early-onset familial Alzheimer’s disease (FAD).

A further round of functional and positional screening of clones harboring different 16S rRNA segments uncovered a 75bp open reading frame (ORF) sequence that encodes a 24 amino acid peptide called Humanin. Humanin may be translated into either the mitochondria or the cytoplasm.

To create a unique peptide from the same sequence, mitochondria use a slightly modified genetic code, in contrast to the cytoplasmic translation utilized by the rest of the cell. So far, the translational site for Humanin has not been identified, although it has been hinted to be physiologically functional when generated utilizing both mitochondrial and cytoplasmic coding. Humanin ORF cloning and expression in neural cells has been hypothesized to restore its possible protective effects against numerous AD-related toxicities.

One more research team has isolated Humanin as a binding partner of Bax, an essential pro-apoptotic protein that shuttles to the mitochondria to set off the death signal. Their connection seems to result in the Humanin-bax complex being kept in the cytoplasm and, therefore, protected against apoptosis.

It has been suggested that the Humanin peptide sequence contains a “pseudo-signal peptide” because of its potential to be detected in the culture medium after being transfected into neuronal cells. This aspect indicates secretory capacity may be inhibited by blocking endoplasmic reticulum-Golgi transport processes. Several groups have hypothesized that the innate cell surface receptors for Humanin are accurate and functional.

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