How MOTS-c was discovered: the 2015 mitochondrial genome finding
Prepared by: Research Desk. Sources are linked for verification.
Status: Investigational. MOTS-c is not an FDA-approved drug. Our legal status page explains its regulatory and anti-doping position in detail.
MOTS-c is only about ten years old as a named molecule. Before 2015, almost nobody had heard of it, because nobody knew it existed. This page tells the discovery story step by step: where the researchers looked, what they reported, why other scientists paid attention, and what the discovery did not show.
For a broader introduction to what MOTS-c is, start with our beginner's guide, What is MOTS-c?. This page focuses only on the discovery and the research that followed it.
The short version: a timeline
When | What happened | Type of work | Source |
|---|---|---|---|
2015 | Lee and colleagues describe MOTS-c, a short peptide encoded in mitochondrial DNA | Cell and mouse experiments | [1] |
2015 | A separate Cell Metabolism article by Zarse and colleagues is titled "A mitochondrially encoded hormone ameliorates obesity and insulin resistance" | Journal article | [2] |
2018 | A follow-up study reports that MOTS-c moves into the cell nucleus under metabolic stress | Laboratory study | [3] |
2021 | A study describes MOTS-c as exercise-induced and links it to age-related changes in muscle | Research article | [4] |
2023 | An article describes MOTS-c as a "promising" candidate for future therapeutic research | Journal article | [5] |
Current | A human trial of investigational MOTS-c is listed on ClinicalTrials.gov | Trial registration | [6] |
Background: why nobody expected messages hidden in mitochondria
Mitochondria are the small structures inside cells often called "power plants". Unusually, they carry their own small loop of DNA, separate from the main DNA in the cell's nucleus. For decades, this mitochondrial DNA was thought to hold a short, fully mapped list of instructions, almost all of them for parts of the energy-making machinery.
That picture started to shift when researchers began looking more closely for short open reading frames: small stretches of genetic code that could, in principle, be read to build tiny proteins. Some of these stretches sit inside genes that were already known to do something else. The molecules made from them are now called mitochondrial-derived peptides (MDPs), and the 2015 paper describes MOTS-c as one of them [1].
How the 2015 team found MOTS-c
The 2015 study by Lee and colleagues, published in Cell Metabolism, searched mitochondrial DNA for short open reading frames that might encode previously unknown peptides [1]. One candidate sat within the region of the gene for 12S ribosomal RNA, a molecule that is part of the mitochondria's own protein-building machinery.
According to the paper's abstract, the researchers named the new peptide MOTS-c, short for "mitochondrial open reading frame of the 12S rRNA-c", and described it as 16 amino acids long [1]. For comparison, many familiar proteins run to hundreds of amino acids, which is part of why a peptide this small was easy to overlook.
Finding a stretch of code is only the first step. The team also needed to show that the peptide was actually made and that it did something measurable in living systems. That is where the cell and mouse experiments came in.
What the 2015 paper reported
It helps to read the original findings by study type, because each type answers a different question.
Cell experiments. In cultured cells, the authors reported in their abstract that MOTS-c acted on the folate cycle and a linked step in building purines (one of the chemical building blocks of DNA). They connected this to activation of AMPK, an enzyme that acts as a cellular energy sensor [1]. The abstract also names skeletal muscle as the peptide's apparent primary target tissue [1].
Mouse experiments. The authors reported that mice given MOTS-c showed less diet-related weight gain and less insulin resistance on a high-fat diet, and less age-related insulin resistance, compared with control mice [1]. The paper's title summarises these mouse findings as promoting "metabolic homeostasis" and reducing "obesity and insulin resistance" [1].
What the paper did not include. The 2015 study was not a human trial. Its findings describe what was measured in cells and in mice under laboratory conditions. Our guide on what MOTS-c is explains in more detail why mouse results often fail to carry over to people.
Why the discovery got attention
Also in 2015, Cell Metabolism published an article by Zarse and colleagues titled "A mitochondrially encoded hormone ameliorates obesity and insulin resistance" [2]. The word hormone is the key idea. Hormones are messengers that travel from one place to act somewhere else. Describing MOTS-c as a mitochondrially encoded hormone framed it as possible evidence that mitochondria do not just produce energy, but may also send signals to the rest of the cell, and perhaps to other tissues.
That framing is a big reason the discovery drew interest. It suggested a new layer of communication that textbooks had not described. It is still a framing, though: calling something a hormone in a title is an interpretation of early laboratory results, not proof of how it works in people.
What follow-up research added
2018: MOTS-c and the cell nucleus
A 2018 study by Kim and colleagues reported that MOTS-c moves into the cell nucleus in response to metabolic stress and regulates the activity of nuclear genes [3]. This was surprising because it described a molecule encoded in mitochondrial DNA influencing genes stored in the separate nuclear genome. It was a laboratory study, so it describes cell biology, not effects in people.
2021: the exercise connection
Reynolds and colleagues titled their paper "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis" [4]. In other words, the authors linked MOTS-c levels to exercise and studied how it relates to the way muscle changes with age. These are research measurements made under study conditions; they do not describe an established effect of taking MOTS-c in humans.
2023: discussing the field
By 2023, enough work had accumulated for authors to step back and discuss the field as a whole. Zheng and colleagues described MOTS-c as "a promising mitochondrial-derived peptide for therapeutic exploitation" [5]. Words like "promising" in an article title signal a research direction that scientists want to explore, not a result shown in people.
What the discovery did not show
A good discovery story also lists its limits. Based on the sources above:
No human efficacy data in 2015. The original findings came from cells and mice [1].
Mechanism is still being mapped. The 2015 AMPK link and the 2018 nucleus finding are pieces of a picture, not a complete explanation [1][3].
"Exercise-induced" is not "exercise replacement". The 2021 work describes MOTS-c as exercise-induced, but that does not mean MOTS-c reproduces the effects of exercise in people [4].
Safety in humans was not established. None of these discovery-era papers was designed to measure safety in people.
From the lab to registered human research
A decade after the discovery, MOTS-c has moved from a basic-science finding into registered human research. A trial listed on ClinicalTrials.gov (NCT07505745) is studying investigational MOTS-c for insulin sensitivity in adults with prediabetes and overweight or obesity [6]. The registry record is the place to check its design, dates and current status. A registered trial means a question is being tested; it does not mean the answer is known.
Sport has its own rules. The World Anti-Doping Agency publishes its Prohibited List, which is the official reference for the substances and classes of substances banned in sport [7]. Our page Is MOTS-c legal? walks through FDA approval status and anti-doping rules in plain English.
Frequently asked questions
Who discovered MOTS-c?
MOTS-c was first described in a 2015 Cell Metabolism paper by Lee and colleagues [1]. The team found it by searching mitochondrial DNA for short stretches of genetic code that could build small, previously unknown peptides.
Was MOTS-c discovered in humans or mice?
The 2015 paper describes MOTS-c as encoded in mitochondrial DNA and reports experiments in cultured cells and in mice [1]. Cells grown in a dish are not the same as human participants. A registered trial is now studying investigational MOTS-c in adults [6].
Does the discovery mean MOTS-c is approved or proven?
No. A discovery shows that a molecule exists and does something measurable in a lab, not that it is safe or effective in people. MOTS-c remains investigational and is not an FDA-approved drug; a human trial is listed on ClinicalTrials.gov [6].
Further reading on cells and mitochondria
Discovery stories like this one make much more sense with a solid grounding in basic cell biology. A well-chosen introductory book is one of the most cost-effective ways to learn what mitochondria, genes and cellular energy sensors actually are. When comparing options, these neutral criteria are useful:
Publication date. Mitochondrial signalling is a fast-moving field, so check the edition year and whether recent findings are covered.
References. Books that cite primary studies are easier to verify than books that rely on anecdotes.
Evidence labelling. Prefer books that clearly separate established cell biology from hypotheses and animal-only findings.
Reading level and format. Compare print, ebook and audiobook options, and check whether diagrams are included, since cell biology is very visual.
Price transparency. Compare edition prices and check whether a cheaper earlier edition still covers the basics.
Red flags. Skip titles that promise personal health outcomes or sell a product inside the book.
A good book builds background knowledge; it does not replace reading the original studies listed below, which remain the best way to check any claim.
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Last updated: 19 October 2026.
Related on this site
Is MOTS-c legal? FDA status and anti-doping rules, simply explained
Best books on mitochondria for beginners: a 2026 reading list
How to evaluate MOTS-c claims online: a beginner's checklist
Exercise and MOTS-c: what the research shows, in plain English
MOTS-c vs NAD+: two very different molecules in metabolism research
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