1. Introduction
Mitochondria have long been recognised as the principal generators of cellular energy through oxidative phosphorylation, yet their role as active signalling organelles has only recently gained widespread appreciation. The discovery of mitochondrial-derived peptides (MDPs) — small bioactive peptides encoded within the mitochondrial genome — has fundamentally expanded the understanding of retrograde mitochondrial-to-nuclear communication. Among these, MOTS-c (Mitochondrial Open Reading Frame of the Twelve S rRNA type-c) has emerged as a particularly significant molecule, representing the first mitochondrial-encoded peptide demonstrated to regulate nuclear gene expression and systemic metabolic function (Lee et al., 2015).
MOTS-c is a 16-amino acid peptide (MRWQEMGYIFYPRKLR) encoded within the 12S rRNA gene (MT-RNR1) of the mitochondrial DNA. Its identification by Lee and colleagues in 2015 marked a paradigm shift in mitochondrial biology, demonstrating that the mitochondrial genome encodes functional peptide hormones capable of influencing whole-body physiology (Lee et al., 2015). Since its discovery, MOTS-c has attracted considerable research interest due to its apparent roles in metabolic homeostasis, insulin sensitisation, exercise adaptation, and age-related physiological decline. This review examines the current state of MOTS-c research, with particular attention to its molecular mechanisms, metabolic regulatory functions, and exercise mimetic properties.
2. Origin and Classification as a Mitochondrial-Derived Peptide
MOTS-c belongs to a growing family of mitochondrial-derived peptides, which also includes Humanin and the small Humanin-like peptides (SHLPs). These peptides are encoded within small open reading frames (sORFs) embedded in the mitochondrial genome — regions previously assumed to be functionally inert (Miller et al., 2020). Unlike the 13 well-characterised proteins encoded by mitochondrial DNA that function within the electron transport chain, MDPs are translated from novel sORFs and appear to serve primarily as signalling molecules rather than structural components of the respiratory machinery (Kim et al., 2017).
The discovery of MDPs has raised important questions about the informational capacity of the mitochondrial genome. The 16,569-base-pair human mitochondrial genome was traditionally thought to encode only 37 genes (13 proteins, 22 tRNAs, and 2 rRNAs). The identification of functional sORFs within rRNA sequences suggests that the coding potential of this compact genome has been substantially underestimated (Miller et al., 2020). MOTS-c is translated from a sORF within the 12S rRNA, and its sequence is partially conserved across species, suggesting functional importance maintained through evolutionary pressure (Lee et al., 2015).
Population genetic studies have identified naturally occurring polymorphisms in the MOTS-c coding sequence, most notably the m.1382A>C variant (resulting in a K14Q amino acid substitution), which is prevalent in East Asian populations. This variant has been associated with increased susceptibility to type 2 diabetes and related metabolic parameters, providing human genetic evidence that endogenous MOTS-c variation has physiologically meaningful consequences (Zempo et al., 2021).
3. Molecular Mechanisms: AMPK Activation and the Folate-Methionine Cycle
The primary intracellular signalling axis through which MOTS-c exerts its metabolic effects involves the activation of 5'-AMP-activated protein kinase (AMPK), a central cellular energy sensor. Lee et al. (2015) demonstrated that MOTS-c treatment in cultured cells leads to substantial AMPK phosphorylation, accompanied by downstream effects including enhanced glucose uptake and fatty acid oxidation (Lee et al., 2015). AMPK activation by MOTS-c appears to be secondary to the peptide's effects on one-carbon metabolism, specifically its inhibition of the folate cycle at the level of 5-methyl-tetrahydrofolate (5-Me-THF), which leads to accumulation of the intermediate AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), an endogenous AMPK activator.
This mechanistic pathway is notable because it positions MOTS-c at the intersection of two fundamental metabolic networks: mitochondrial energy sensing and one-carbon metabolism. The folate-methionine cycle supplies methyl groups essential for DNA methylation, histone modification, and nucleotide biosynthesis. By modulating flux through this pathway, MOTS-c may influence not only acute energy metabolism but also epigenetic regulation and cellular proliferation (Lee et al., 2015). The accumulation of AICAR as a consequence of folate cycle disruption provides a mechanistic explanation for MOTS-c's AMPK-activating capacity, as AICAR is a well-established pharmacological AMPK agonist that mimics the effects of elevated AMP:ATP ratios.
Subsequent research has extended the understanding of MOTS-c's nuclear signalling activities. Reynolds et al. (2021) demonstrated that in response to metabolic stress, MOTS-c translocates to the nucleus, where it interacts with transcription factors and modulates the expression of antioxidant response element (ARE)-regulated genes. This nuclear translocation is AMPK-dependent and positions MOTS-c as a direct mediator of mitonuclear communication — a retrograde signal by which the mitochondria can adaptively regulate nuclear gene expression in response to metabolic demand (Reynolds et al., 2021).
4. Exercise Mimetic Properties
One of the most striking aspects of MOTS-c biology is its characterisation as an exercise mimetic — a compound that recapitulates certain molecular and physiological adaptations normally produced by physical activity. This designation arises from multiple converging lines of evidence. First, circulating MOTS-c levels have been observed to increase in response to acute exercise in both murine models and human subjects, suggesting that MOTS-c is part of the endogenous exercise response (Reynolds et al., 2021). Second, exogenous MOTS-c administration in sedentary mice has been reported to improve exercise capacity, enhance physical performance, and attenuate age-related physical decline without the animals engaging in physical training.
Reynolds et al. (2021) provided particularly compelling evidence for the exercise mimetic designation. In aged mice (approximately 22 months old), MOTS-c treatment improved running endurance, grip strength, and overall physical performance on treadmill tests. Gene expression analyses of skeletal muscle from MOTS-c-treated mice revealed upregulation of pathways associated with myofibre integrity, mitochondrial biogenesis, and stress resistance — profiles that substantially overlapped with gene expression changes observed following exercise training (Reynolds et al., 2021). These findings suggest that MOTS-c may activate conserved adaptive pathways that are ordinarily engaged by physical activity, potentially through the AMPK-dependent signalling cascade described above.
The skeletal muscle effects of MOTS-c extend beyond performance enhancement. Kumagai et al. (2021) investigated the relationship between MOTS-c and muscle atrophy signalling, demonstrating that the peptide reduces expression of myostatin — a negative regulator of muscle growth — and attenuates markers of muscle wasting in experimental models. These observations suggest that MOTS-c may function not only to improve active performance but also to maintain muscle mass and quality, particularly during conditions associated with disuse or ageing (Kumagai et al., 2021).
5. Metabolic Homeostasis and Insulin Sensitisation
The metabolic effects of MOTS-c were central to its initial characterisation. In the foundational study by Lee et al. (2015), exogenous MOTS-c administration in mice prevented age-dependent and high-fat diet-induced insulin resistance, reduced body weight gain, and improved glucose disposal as measured by glucose tolerance and insulin tolerance tests. These effects were attributed to enhanced skeletal muscle glucose uptake through AMPK-dependent GLUT4 translocation, as well as increased fatty acid beta-oxidation (Lee et al., 2015).
The insulin-sensitising properties of MOTS-c have been further explored in multiple metabolic contexts. Kim et al. (2019) described MOTS-c as an "equal opportunity insulin sensitizer," noting its capacity to improve insulin sensitivity across diverse tissue types and metabolic conditions (Kim et al., 2019). Lu et al. (2019) extended these findings to a model of ovariectomy-induced metabolic dysfunction, demonstrating that MOTS-c administration could mitigate the metabolic disturbances associated with oestrogen deficiency, including excessive adipose tissue accumulation and impaired glucose homeostasis (Lu et al., 2019). These results are particularly noteworthy because they indicate that MOTS-c's metabolic effects are not confined to dietary models of obesity but may extend to hormonally driven metabolic perturbations.
At the cellular level, Mangalhara et al. (2022) investigated MOTS-c as a biomarker and functional correlate of mitochondrial metabolic status. Their research demonstrated that endogenous MOTS-c levels reflect the metabolic state of the mitochondria, and that perturbations in mitochondrial function — whether through genetic manipulation or pharmacological intervention — produce measurable changes in MOTS-c expression. This bidirectional relationship between mitochondrial health and MOTS-c abundance suggests that the peptide serves as both an effector and an indicator of mitochondrial metabolic competence .
6. Ageing and Longevity Research
The intersection of MOTS-c biology with ageing research represents one of the most active areas of current investigation. Circulating MOTS-c levels have been reported to decline with age in both rodent models and human cohorts, mirroring the age-dependent decline in mitochondrial function and metabolic flexibility . This correlation has prompted the hypothesis that declining MDP levels may contribute to the metabolic deterioration characteristic of ageing, and that exogenous restoration of these peptides might attenuate age-related physiological decline.
Yen et al. (2020) reviewed the roles of both Humanin and MOTS-c as potential regulators of ageing and longevity, noting that both peptides decline with age and both exert protective effects in models of age-related pathology. The authors suggested that MDPs may constitute an endogenous defence system against the metabolic consequences of mitochondrial ageing, and that their therapeutic restoration could represent a novel approach to promoting healthy ageing . However, it should be noted that the causal relationship between MDP decline and ageing phenotypes remains to be definitively established, and current evidence is largely correlative and derived from preclinical models.
7. Current Directions and Limitations
Research into MOTS-c continues to expand along several fronts. Ongoing investigations are examining the peptide's pharmacokinetics, tissue distribution, and dose-response relationships in greater detail. The nuclear translocation mechanism identified by Reynolds et al. (2021) has opened new avenues for understanding how mitochondrial signals are integrated into nuclear transcriptional programmes, and chromatin immunoprecipitation studies are beginning to map the genomic loci influenced by MOTS-c nuclear activity (Reynolds et al., 2021).
The population genetics of MOTS-c represent another active research area. The identification of the K14Q polymorphism and its association with metabolic disease risk has stimulated interest in whether MOTS-c variants contribute to population-level differences in metabolic disease susceptibility, exercise capacity, or ageing trajectories (Zempo et al., 2021). Such studies may ultimately reveal whether MOTS-c sequence variation interacts with environmental factors such as diet and physical activity to modulate health outcomes.
Several important limitations of the current MOTS-c literature warrant acknowledgement. The majority of mechanistic and efficacy data derive from murine models and cell culture systems, and extrapolation to human physiology must be approached with appropriate caution. The precise mechanisms by which circulating MOTS-c enters target cells and reaches the nucleus remain incompletely characterised. Additionally, the long-term safety profile of exogenous MOTS-c administration has not been established in any species. As with all mitochondrial-derived peptide research, the field is relatively young, and many foundational questions regarding peptide processing, secretion, receptor interactions, and tissue-specific effects remain to be resolved (Kim et al., 2017).
8. Conclusion
MOTS-c represents a remarkable addition to the expanding catalogue of bioactive molecules encoded within the mitochondrial genome. Its capacity to activate AMPK through modulation of one-carbon metabolism, translocate to the nucleus to regulate gene expression, and recapitulate key molecular signatures of exercise adaptation positions it as a uniquely multifaceted peptide at the intersection of mitochondrial biology, metabolic regulation, and exercise physiology. Preclinical evidence supporting its roles in insulin sensitisation, exercise capacity enhancement, muscle preservation, and protection against age-related metabolic decline provides a compelling foundation for continued investigation. Nevertheless, the translation of these findings to human applications remains in its early stages, and rigorous clinical investigation will be essential to determine whether the promising preclinical profile of MOTS-c extends to human physiology and disease.