Abstract
A comprehensive review of MOTS-c, the mitochondrial-derived exercise mimetic peptide that activates AMPK, translocates to the nucleus during metabolic stress, and demonstrates remarkable effects on metabolism, physical performance, and aging in preclinical models.
MOTS-c, which stands for Mitochondrial Open Reading Frame of the Twelve S ribosomal RNA type-c, is a 16-amino acid peptide with the sequence MRWQEMGYIFYPRKLR, encoded within the 12S rRNA gene of mitochondrial DNA. It was first described in 2015 by a research team at the University of Southern California led by Dr. Changhan David Lee and Dr. Pinchas Cohen, who identified it as an evolutionarily conserved signaling molecule with profound metabolic effects. The discovery of MOTS-c was groundbreaking because it demonstrated that the mitochondrial genome, long thought to encode only 13 structural proteins for oxidative phosphorylation plus ribosomal and transfer RNAs, actually encodes small bioactive peptides capable of regulating systemic physiology.
MOTS-c belongs to the family of mitochondrial-derived peptides, sharing this classification with humanin and SHLP1-6 (small humanin-like peptides). However, MOTS-c is unique in that it is encoded by the 12S rRNA gene rather than the 16S rRNA gene that encodes humanin. It is also the first mitochondrial-encoded peptide shown to translocate to the nucleus during metabolic stress, where it directly regulates gene expression. This nuclear translocation, described in a 2018 study by Kim and colleagues, represents a novel form of retrograde mitochondrial-to-nuclear communication and fundamentally expanded our understanding of how mitochondria influence cellular fate.
The primary mechanism of action of MOTS-c centers on activation of AMP-activated protein kinase, known as AMPK, which functions as the master metabolic sensor and regulator of cellular energy homeostasis. When MOTS-c activates AMPK, it triggers a cascade of metabolic effects including increased glucose uptake into cells, enhanced fat oxidation and lipid metabolism, stimulation of mitochondrial biogenesis through upregulation of PGC-1alpha and TFAM, promotion of autophagy for cellular cleanup and renewal, and reduction of inflammatory signaling. In cultured cells, MOTS-c treatment alters the metabolite profile within 4 hours, with changes consistent with regulation of the folate cycle, an effect also seen with other AMPK activators such as the diabetes drug metformin.
Perhaps the most striking characteristic of MOTS-c is its function as an exercise mimetic. Exercise itself induces MOTS-c expression in muscle cells, with levels increasing nearly 12-fold in mouse skeletal muscle following physical activity and plasma levels rising approximately 50 percent during and after exercise. When administered exogenously, MOTS-c reproduces many of the physiological benefits of exercise. In aged mice equivalent to 65 or older in human years, MOTS-c treatment doubled running capacity and allowed treated elderly mice to outperform untreated middle-aged counterparts. Treated mice showed improved grip strength, increased stride length, and enhanced balance on performance tests. Even mice fed high-fat diets demonstrated marked physical improvement with less weight gain when receiving MOTS-c. These findings are particularly significant because late-life interventions are more translationally feasible than lifelong treatments.
The metabolic effects of MOTS-c extend well beyond exercise mimicry. The peptide prevents weight gain and reduces body weight in diet-induced obesity models without affecting food intake. Instead, it increases energy expenditure through enhanced thermogenesis and increased carbohydrate utilization. In the liver, MOTS-c reduces lipid accumulation by diminishing mitochondrial stress and promoting beta-oxidation of fatty acids. Treatment reverses high-fat diet-induced insulin resistance in mice, improves glucose tolerance, and restores insulin sensitivity, with effects comparable to exercise intervention. In senescent human fibroblasts, MOTS-c enhances beta-oxidation and mitochondrial respiration, indicating that it can restore metabolic function even in aged cells.
MOTS-c demonstrates significant effects on musculoskeletal health beyond physical performance. In bone metabolism research, mice treated with 5 mg per kg per day of MOTS-c via intraperitoneal injection for 12 weeks showed reduced bone loss through inhibition of osteoclast formation via AMPK-mediated suppression of RANKL, the primary mediator of osteoclast differentiation. In primary cell culture, MOTS-c induces osteogenesis and mineralization in bone marrow stromal cells through activation of FOXF1 and TGF-beta signaling pathways, suggesting potential for bone repair and strengthening. The peptide may also promote type I collagen synthesis through the TGF-beta/Smad pathway.
Cardiovascular protective effects have been documented in multiple models. MOTS-c improves endothelial function, reduces risk factors for atherosclerosis, protects against ischemia-reperfusion injury, inhibits vascular calcification, and attenuates myocardial remodeling. A 2024 study demonstrated that MOTS-c treatment produces antiallodynic effects, alleviating pain caused by non-noxious stimuli in inflammatory conditions, and significantly ameliorated inflammatory factors and responses in affected tissues.
The immune-enhancing effects of MOTS-c are notable. In a bacterial infection model, MOTS-c administered 2 hours after infection improved survival from 50 percent to 100 percent. Treated mice showed reduced bacterial loads, dampened proinflammatory cytokine responses, and increased bactericidal capacity of macrophages evidenced by increased expression of the pattern recognition receptor dectin-1.
MOTS-c also shows neuroprotective properties, protecting against amyloid-beta-42 and lipopolysaccharide-induced memory impairment on cognitive tasks in mice. However, because MOTS-c does not efficiently cross the blood-brain barrier, cognitive benefits were observed only when the peptide was administered centrally via intracerebroventricular injection, representing a limitation for translational neurological applications.
Endogenous MOTS-c levels decline with age, and this decline correlates with deterioration in metabolic health, physical performance, and tissue function. The age-related reduction in MOTS-c parallels the broader decline in mitochondrial function that is a hallmark of aging, suggesting that MOTS-c depletion may contribute to age-related metabolic dysfunction.
The clinical research status of MOTS-c is still early. The peptide itself has not been tested in human clinical trials as a therapeutic agent. The only human clinical evidence comes from a Phase 1a/1b trial of CB4211, a MOTS-c analog developed for clinical application, which was tested in healthy volunteers and a subset with non-alcoholic fatty liver disease. The CB4211 analog was found to be safe in short-term studies, though persistent injection site reactions were common. The safety profile of exogenous MOTS-c has not been established in humans, and its potential interactions with drugs that target AMPK, such as metformin, have not been thoroughly evaluated. Despite these limitations, the breadth and consistency of preclinical evidence positions MOTS-c as one of the most promising peptide candidates for metabolic health and longevity applications.
