Scientists have described eight MDPs: humanin, MOTS-c and six small humanin-like peptides (SHLP1 to SHLP6). Research has focused on different aspects of their activity. Humanin has been studied in models of cell injury, MOTS-c in metabolic experiments, and several SHLPs in work involving insulin signaling and cellular stress. Most of this work has been done in cell cultures and animals. In people, researchers have mostly measured the MDPs the body makes by itself. What happens when you administer them to humans has barely been studied.

Where the peptides came from

There are 37 recognized genes in human mitochondrial DNA, and 13 of them carry instructions for making proteins used in energy production. The others encode RNA: 22 transfer RNAs and two ribosomal RNAs, all needed for mitochondrial protein synthesis. For years, researchers thought they had mapped the genome's entire coding capacity. They had missed something, though. The tools used to identify genes were better at finding longer sequences, leaving some very short peptide-coding regions undetected.

Humanin was the first surprise. In 2001, a team studying neuronal cells and Alzheimer’s disease reported that a short sequence linked to mitochondrial ribosomal RNA encoded a peptide with real biological activity. Later work tested it in models of cell injury and programmed cell death.

MOTS-c came in 2015. It’s 16 amino acids long and comes from the 12S rRNA region (hence the name: mitochondrial open reading frame of the 12S rRNA-c). The six SHLPs were described in 2016 by another group, this time from the 16S rRNA region.

Scientists have yet to determine whether mitochondrial DNA encodes other peptides. Identifying a short coding sequence doesn't establish that it produces a functional molecule. Researchers need evidence that the peptide is made in cells, information about where it occurs and experiments showing its biological activity.

MOTS-c and metabolism

MOTS-c was first described in a 2015 paper in Cell Metabolism (Lee et al.). The experiments used cultured cells and mice and focused on energy balance and insulin sensitivity.

MOTS-c changed two metabolic processes in the cultured cells: folate metabolism and purine synthesis. Both are involved in making molecules that cells need to function. The researchers also observed activation of AMPK (AMP-activated protein kinase). This enzyme helps cells manage their energy supply, adjusting glucose uptake and fat metabolism when available energy runs low.

The mouse results were more tangible. Treated mice responded better to insulin, and those on a high-fat diet put on less weight. Skeletal muscle looked like a key tissue in all this. Older mice got a boost in metabolic measures too.

Worth being precise about what that proves. MOTS-c influenced metabolic pathways in certain animal models. Nobody tested whether the same would happen in people.

From mitochondria to the nucleus

A 2018 study examined how MOTS-c behaves when cells experience metabolic stress. Researchers found that the peptide could move into the nucleus and interact with chromatin, the material that packages DNA. This was accompanied by changes in the expression of genes involved in cellular stress responses.

The experiments offered evidence of communication between mitochondria and the nucleus through MOTS-c. Researchers observed changes in gene activity under specific laboratory conditions, although the extent of this mechanism in different human tissues remains unclear.

Humanin and the SHLPs

Humanin was discovered back in 2001. The first experiments involved nerve cells exposed to conditions associated with Alzheimer's disease. Researchers then began looking at its interaction with proteins that regulate apoptosis, or programmed cell death. Some experiments found that humanin reduced cell injury. Others examined what it does in models of metabolic disorders and cardiovascular stress, although the results have varied with the experimental conditions.

Outcomes depend on the model, though. A peptide that shields cultured neurons hasn’t been shown to prevent neurological disease in people, and the two shouldn’t be conflated.

The SHLPs are less well charted. Some have been checked for effects on mitochondrial activity, insulin signaling and cell survival, and SHLP2 and SHLP3 have attracted most of the interest in metabolic experiments. A few studies report shifts in insulin-related responses. They share an origin, but they don’t act the same way, so a result with one SHLP can’t be handed to the others.

For a wider look, a 2024 review in Peptides covers what MDPs do in metabolism, including glucose regulation and cell protection, and lists what’s still unresolved about how mitochondrial genetics links to peptide activity.

Why researchers care about MDP signaling

Mitochondria react to everything: nutrient supply, oxygen, how hard the cell is working. Cells already have several ways to pass that information on, among them calcium signaling, reactive oxygen species and metabolites made in the mitochondria. MDPs could be one more. They’re unusual because the mitochondrial genome itself encodes them, and that’s exactly why people who study communication between mitochondria and the nucleus find them so appealing.

A lot is still unanswered:

• What controls how much of each MDP is made?
• Do peptide levels change in a predictable way under particular kinds of stress?
• How do they get from one compartment, or tissue, to another?
• Does variation in mitochondrial DNA change peptide production or activity?

Some human studies have measured circulating MDPs, which could eventually connect peptide levels to age and metabolic conditions. There’s a catch. If two groups differ in blood levels, you can’t tell from that alone whether the peptide caused a change or responded to one. Both possibilities have to be tested.

How research peptide quality affects experimental results

The reliability of peptide research depends not only on experimental methods but also on the quality of the materials being tested. Differences in peptide identity, purity or batch composition can affect the results, making it harder to determine whether an observed effect comes from the peptide itself or from something else in the sample.

Two methods are used most. HPLC (high-performance liquid chromatography) separates a sample’s components by how they interact with the system, which gives an estimate of chromatographic purity and can reveal some impurities, though only the ones the method can detect. Mass spectrometry measures mass-to-charge ratios, which supports identity testing and, depending on the technique, can say something about structure.

Then there’s the certificate of analysis (COA), which documents results for one specific production batch. It shows which tests were run and lets a lab confirm that the material it received matches the batch on paper.

Purity and identity are separate questions. A sample can show high HPLC purity and still need independent confirmation that its main component is the intended peptide. Laboratories planning to buy MOTS-c peptide for research purposes should read the available analytical documentation and check that it corresponds to the batch being supplied. It matters later, too. When two experiments disagree, a different batch, and a different composition, is one of the first things to rule out.

What the evidence doesn’t show yet

This field has uncovered biological activities nobody had connected to the mitochondrial genome before. MOTS-c has been tied to metabolic signaling in cells and mice, humanin has been examined in models of cell injury, and several SHLPs have shown activity in metabolic experiments.

The evidence is lopsided, though. A few of these peptides have been tested in many systems; others have only a handful of papers. Human studies of naturally occurring MDPs add another kind of data, because concentrations can be measured and compared with physiological traits. They can’t tell us whether administering synthetic versions would be safe or effective.

Several basic questions remain: how MDPs are produced, how long they stay active, whether findings from animal models carry over to human biology. Any clinical use would need far more work. For now, MDPs belong to basic and preclinical research. MOTS-c, humanin and the SHLPs are not established treatments, and the materials discussed here are for laboratory use only, not for human consumption or clinical administration.

References

Lee C., Zeng J., Drew B.G., et al. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism, 21(3), 443–454.
https://doi.org/10.1016/j.cmet.2015.02.009

Kim K.H., Son J.M., Benayoun B.A., Lee C. (2018). The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metabolism, 28(3), 516–524.e7.
https://doi.org/10.1016/j.cmet.2018.06.008

Hashimoto Y., Niikura T., Tajima H., et al. (2001). A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Aβ. Proceedings of the National Academy of Sciences, 98(11), 6336–6341.
https://doi.org/10.1073/pnas.101133498

Cobb L.J., Lee C., Xiao J., et al. (2016). Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging, 8(4), 796–809.
https://doi.org/10.18632/aging.100943

Kim K.H., Lee C. (2024). Mitochondrial-derived peptides: Antidiabetic functions and evolutionary perspectives. Peptides, 172, 171147.
https://doi.org/10.1016/j.peptides.2023.171147