Typically, mitochondria are presented as the organelles that produce most of the energy a cell can use. That is the correct description, but it’s not complete. In the last two decades, it has been found that mitochondria are also involved in cellular signalling, stress, inflammation and metabolic regulation. What has been interesting is the finding of small peptides encoded by the mitochondrial DNA.
One of these molecules is called MOTS-c. Since it was first described in 2015, researchers have investigated its potential role in metabolic homeostasis, cellular stress adaptation, glucose regulation and age-related physiological changes.
Interest in MOTS-c research in the UK forms part of a broader scientific focus on mitochondrial-derived peptides and the signals that allow mitochondria to communicate with the rest of the cell. But most of the findings are still experimental. MOTS-c should thus be considered an experimental research molecule and not as a proven treatment.
What Is MOTS-c?
MOTS-c stands for mitochondrial open reading frame of the 12S rRNA type-c. It is a small peptide composed of 16 amino acids and encoded within the mitochondrial 12S rRNA region.
What makes MOTS-c unusual is its origin.
Most proteins that work in mitochondria are made in the cell nucleus. Their genes are located in the nuclear genome, they are translated in the cytoplasm, and the resulting proteins are subsequently imported into mitochondria. MOTS-c is one of a handful of peptides derived from mitochondrial DNA.
Its discovery has helped overturn the previous notion that mitochondrial DNA played only a limited protein-coding function.
Mitochondrial-derived peptides are now being investigated as signalling molecules that may influence processes beyond energy production. MOTS-c has garnered special interest since experiments link it to metabolic and cellular stress adaptation pathways.
Why Are Researchers Interested in MOTS-c?
Much of the scientific interest in MOTS-c centres on metabolic flexibility.
Cells continually regulate their access and utilisation of energy. The availability of nutrients, physical activity, oxidative stress, and fasting as well as other environmental factors can alter the energy demands of cells. In order to maintain metabolic balance, communication between many pathways is necessary.
Mitochondria sit at the centre of this regulatory network.
Mitochondria do not just serve as passive generators of energy but also can send signals based on the metabolic status of the cell. MOTS-c is one mitochondrial-derived peptide being investigated for a possible role in this communication.
These areas overlap biologically, but findings in them should not be interpreted as evidence that MOTS-c can treat metabolic disease or reverse ageing in humans.
It’s important to differentiate between a research discovery and a clinical benefit.
MOTS-c and Cellular Metabolism
A very early field of study in MOTS-c research was the study of metabolic regulation.
Early laboratory and animal studies indicated that MOTS-c has the potential to affect pathways involved in glucose utilisation and energy balance. Some of these effects have been proposed to be mediated by changes in folate and purine metabolism, subsequently impacting on key pathways that sense cell energy.
One pathway of particular interest is AMP-activated protein kinase (AMPK), a central cellular energy sensor.
AMPK functions in a somewhat similar manner to a cell fuel sensor. If energy is becoming a limiting factor for cells, AMPK aids in redirecting energy to pathways that produce energy and limiting some pathways that consume energy.
Under specific experimental conditions, MOTS-c activity has been associated with AMPK signalling. This could be one pathway by which the peptide may affect metabolic adaptation.
The situation is not so straightforward as MOTS-c switching AMPK ‘on’. Cellular metabolism is a series of connected pathways and effects observed depend on the experimental model, tissue and metabolic conditions studied.
Research Into Glucose Regulation
Another key research interest of MOTS-c is glucose metabolism.
Preclinical studies have investigated the peptide’s effects on glucose utilisation and metabolic processes associated with insulin resistance. Experimental MOTS-c administration has been shown to improve experimental metabolic parameters in some animal models.
These results have sparked a lot of research and interest, as impaired glucose regulation is linked to obesity, metabolic syndrome and type 2 diabetes.
There is however a caveat.
Results from cell cultures or animal studies can’t necessarily be extrapolated to humans. Animal models can be used to study the biological mechanisms under controlled conditions, but in humans, metabolism is genetically different and affected by a variety of factors such as diet, behaviour, age, medication, and the environment.
Because of this, MOTS-c is still under investigation for metabolic research studies, and not a proven way to manage blood glucose levels.
A Link Between Mitochondria and the Nucleus
The behavior of MOTS-c biology during cellular stress could be interesting.
It has been shown that under certain stress conditions MOTS-c can translocate to the nucleus. There, it seems to have the capacity to interact with regulatory nuclear processes to adapt the cell.
This is scientifically important because mitochondria and the nucleus rely on continuous, coordinated communication.
Mitochondria, while having their own small genome, have a large proportion of proteins that are specific to the mitochondria and are not encoded in the nuclear genome. Therefore, there is a need for synchronised signals between these two genetic systems for the cells to survive.
In MOTS-c, researchers have a potential example of retrograde signalling information flowing from mitochondria to the nucleus and influencing nuclear responses.
This has led to a greater interest than metabolism alone in MOTS-c.
MOTS-c and Cellular Stress
Metabolic, oxidative and environmental stress are regular occurrences in the life of cells. They have to sense these events and respond by changing the activity of cells to ensure their survival.
A potential part of this adaptive response has been investigated as MOTS-c.
Laboratory results suggest that cellular stress can influence the location and activity of MOTS-c, so scientists are also studying to determine if the peptide plays a role in the mechanisms that keep cells in balance under stress.
This concept is sometimes discussed in the context of ‘mitohormesis’.
Hormesis refers to a biological response in which a relatively low-level stressor activates protective/adaptive pathways. In the context of mitochondria studies, it may be beneficial to induce stress under controlled conditions to trigger mechanisms to enhance cellular resilience.
Within this context the functional role of MOTS-c is being investigated, but the role of these mechanisms in humans is still being investigated.
Exercise and Skeletal Muscle Research
The skeletal muscle is a highly metabolically active organ that can be used as a model for investigation of mitochondrial signalling.
It has been studied whether the level of MOTS-c changes or its activity in connection with physical exercise. Preliminary human research suggests that circulating endogenous MOTS-c may respond to exercise, while animal experiments have explored its possible effects on skeletal muscle metabolism and physical performance.
The peptide’s effects on physical performance and skeletal muscle metabolism have also been studied in animals.
This is a fascinating finding since exercise induces rapid changes in glucose uptake, mitochondrial activity and energy sensing. It is possible that some of these responses are mediated via a mitochondrial-derived signalling molecule.
But if a molecule is found to be involved in exercise physiology, this does not mean that it is also possible to mimic these exercise effects if it is administered externally as MOTS-c.
Exercise has multiple, simultaneous effects on the cardiovascular system, skeletal muscle, hormones, metabolism, the nervous system and other biological systems. It would therefore be too simplistic to attribute these adaptations to the action of a single peptide.
MOTS-c and Ageing Research
The function of the mitochondria also varies depending on age, and so researchers have looked at mitochondrial-derived peptides in ageing models.
MOTS-c has been of prime interest in this context due to alterations in metabolic regulation, stress resistance and mitochondrial signalling during ageing.
Several studies have examined whether circulating MOTS-c levels differ according to age, metabolic status or physical condition. Animal studies have also explored its relationship with age-related changes in metabolism and physical function.
The observations have stimulated interest in the discussion of MOTS-c in the field of longevity research.
They do not, however, provide evidence for the ability to extend lifespan or reverse biological ageing in humans with MOTS-c.
There are many processes that are intertwined, such as genomic instability, altered nutrient sensing, cellular senescence, alterations in protein homeostasis and mitochondrial dysfunction that drive ageing. No single signalling molecule is sufficient to explain the complex biology of ageing, let alone provide a solution to it.
For that reason, descriptions of MOTS-c as an established ‘anti-ageing peptide’ go well beyond the available evidence.
What Does Human Research Tell Us?
The evidence base for MOTS-c is not as extensive in humans as in laboratory and animal research.
Naturally occurring MOTS-c has been measured in humans, and researchers have investigated associations with age, metabolic health and exercise. Mitochondrial variants in the sequence of MOTS have also been investigated genetically with respect to their possible association with metabolic features and/or longevity in specific populations.
These studies can give clues to the biological function.
However, these observational findings cannot establish that administering exogenous MOTS-c would reproduce the same biological effects.
It is important in the context of peptide research. An endogenous molecule can have an important physiological function without necessarily being safe or effective when administered as a therapeutic agent.
Controlled human studies would be necessary to establish the pharmacology, safety, dose-response and possible clinical relevance.
MOTS-c UK Research Context
Growing interest in MOTS-c research in the UK reflects broader developments in mitochondrial biology, metabolic research and peptide science.
For UK researchers, an important distinction exists between MOTS-c as an experimental research peptide and its presentation as a medicine or consumer health product.
All research materials should be clearly identified, pure and batch data should be clearly indicated. Depending on the study and supplier documentation, peptide samples can be characterised by analytical methods like HPLC or mass spectrometry.
A Certificate of Analysis can provide useful batch-specific information, but researchers should check which analytical tests were actually performed. A CoA does not necessarily demonstrate every aspect of identity, purity or quality.
MOTS-c sold for laboratory investigation should not be confused with an authorised medicine.
Limitations of Current MOTS-c Research
Overall, the MOTS-c research is encouraging, and there is need for further study, however there are some limitations in the evidence.
Much of the mechanistic evidence is obtained from cell culture and animal models. The human datasets are much smaller and studies can explore natural, not administered, MOTS-c.
It is also important to determine the variations in findings between different tissues, metabolic states and experimental conditions. Signalling mechanisms, pharmacokinetics, and long-term effects remain unknown, as do the significance of specific lab results for human physiology.
Public enthusiasm around MOTS-c sometimes runs ahead of the available scientific evidence. The use of phrases like “fat-burning”, “exercise mimetic”, “anti-ageing” or ‘metabolism-boosting’ can give the impression that a level of certainty exists which is not justified by current research findings.
The Future of MOTS-c Research
MOTS-c has sparked an intriguing field of mitochondrial research.
The significance of its role may not just apply to the action of one 16-amino-acid peptide. MOTS-c will provide researchers with another tool to study the communication between mitochondrial genetic information, metabolic pathways and the nucleus.
To better understand its contributions to metabolic adaptations, exercise physiology, ageing and cellular stress, future studies are warranted. Also, researchers will have to identify which results they see in experimental models are applicable and relevant in humans.
At present, MOTS-c is considered as a novel emerging biologically significant mitochondrial peptide.
It offers strong proof of the role of mitochondria as more than simply ‘cellular power stations’. They play an active role in the signalling pathways that regulate nutrient sensing and cell stress and energy adjustment.
This means that despite the lack of any therapeutic questions to answer yet, MOTS-c is of scientific value. As research progresses, it will be crucial to distinguish real science from preliminary results.
Research-use notice: The discussion here of MOTS-c is for the purposes of science and education. MOTS-c for research is not suitable for human consumption, self-administration, diagnosis or treatment. The conclusions reached in experiments should not be drawn as proof of clinical effectiveness or safety.
