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MOTS-c: Mechanism of Action

MOTS-c is a mitochondrial-encoded peptide that acts as a host defense peptide and metabolic regulator. This article reviews its mechanisms across antibacterial, immunomodulatory, and metabolic pathways, with evidence fro

peptides-pro Editorial

MOTS-c: Mechanism of Action

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a mitochondrial-derived peptide (MDP) encoded within the 12S rRNA gene of mitochondrial DNA. It is also referred to as mitochondrial open reading frame of the 12S rRNA-c. The peptide is amphipathic and cationic, with a sequence of Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg, and a hydrophobicity index of -0.938 [4]. MOTS-c is classified as a host defense peptide (HDP) and a mitokine, exhibiting intracrine, paracrine, and endocrine effects [1][11].

The work on MOTS-c centres on its role as a mitochondrial-encoded regulator of metabolic and inflammatory pathways, with mechanisms involving AMPK activation, NLRP3 inflammasome suppression, and Nrf2 signaling [2][4][9].

Research Studies

MOTS-c and antibacterial host defense

MOTS-c was identified as a mitochondrial-encoded host defense peptide with direct antibacterial and immunomodulatory functions. In vitro studies demonstrated that MOTS-c targets Escherichia coli and other pathogens, consistent with the chemistry of known HDPs [1]. This activity is attributed to its amphipathic and cationic nature, which allows interaction with bacterial membranes. The finding that mtDNA can encode active immune factors challenges the traditional view that the immune system is exclusively nuclear-encoded [1].

MOTS-c and NLRP3 inflammasome suppression in diabetic cardiomyopathy

In a high-fat diet and streptozotocin-induced type 2 diabetes rat model, MOTS-c treatment significantly reduced fasting blood glucose and circulating C-reactive protein levels. It also selectively modulated plasma inflammatory cytokines and suppressed NLRP3 inflammasome activation in systemic and cardiac tissues [2]. These effects suggest a role for MOTS-c in attenuating inflammation associated with diabetic cardiomyopathy.

MOTS-c and LAT1-mediated delivery in radiation-induced lung injury

Wild-type MOTS-c has poor membrane permeability due to its high polarity. An engineered variant, R13A-MOTS-c, was created by substituting arginine at position 13 with alanine, increasing the hydrophobicity index from -0.938 to -0.544. This modification improved cellular uptake via the LAT1 transporter, as confirmed by competition with LAT1 substrates (leucine, BCH) and LAT1 knockdown experiments. In a mouse model of radiation-induced lung injury, R13A-MOTS-c attenuated injury via Nrf2 activation and mitochondrial protection [4].

MOTS-c and atrial fibrillation in human tissue and mouse models

In human atrial tissues and an AngII-induced mouse model, MOTS-c expression was analyzed alongside humanin. Both peptides attenuated atrial fibrillation by suppressing fibrosis and mitochondrial dysfunction. The study used public GEO data, immunohistochemistry, and immunofluorescence to assess expression, and evaluated therapeutic potential in primary cardiac cells [5].

MOTS-c and myocardial ischemia-reperfusion injury in acute myocardial infarction

A cross-sectional study of 72 acute myocardial infarction patients undergoing percutaneous coronary intervention found that serum MOTS-c levels were associated with myocardial ischemia-reperfusion injury (MIRI). Patients were divided into MIRI (n=34) and non-MIRI (n=38) groups, and MOTS-c levels were measured in peripheral serum and intracoronary blood [6]. The study suggests a potential link between MOTS-c and MIRI, though causality remains to be established.

MOTS-c and Hashimoto's thyroiditis

In a cross-sectional study of 90 patients with Hashimoto's thyroiditis compared to age- and sex-matched healthy controls, circulating MOTS-c levels were reduced. The authors concluded that these reduced levels reflect integrated autoimmune and metabolic dysregulation [3]. This association points to a possible role for MOTS-c in thyroid autoimmunity, but the study design does not permit inference of mechanism.

MOTS-c and polycystic ovary syndrome in adolescents

A study investigating serum MOTS-c levels and the m.1382A>C polymorphism in adolescents with polycystic ovary syndrome (PCOS) found differences in MOTS-c levels between PCOS and non-PCOS subjects. The polymorphism was also evaluated for association with serum MOTS-c levels [7]. The m.1382A>C variant has been linked to increased type 2 diabetes risk in men, but this study focused on adolescents with PCOS.

MOTS-c and renal transplantation under different anesthesia techniques

A prospective controlled trial (NCT07678073) is comparing the effects of sevoflurane general anesthesia versus combined spinal-epidural anesthesia on ferroptosis, humanin, and MOTS-c levels in kidney transplant recipients. The study aims to assess whether anesthetic technique influences these biomarkers in the context of ischemia-reperfusion injury [8].

MOTS-c and sepsis-induced cardiomyopathy

A review reports that MOTS-c is implicated in sepsis-induced cardiomyopathy (SICM), a condition characterized by inflammatory dysregulation, mitochondrial dysfunction, and metabolic disturbance. The review discusses mechanisms and translational potential, but does not present new experimental data [9].

MOTS-c and mesenchymal stromal cell function

In human mesenchymal stromal cells (MSCs), MOTS-c activated metabolic signaling but blunted reparative function. This effect was observed in the context of obesity, which compromises MSC metabolism and reparative capacity [10]. The finding suggests a context-dependent role for MOTS-c in cell therapy.

MOTS-c and inflammatory lung diseases

A review discusses MOTS-c as a secreted mitochondrial microprotein with intracrine, paracrine, and endocrine effects. It highlights growing evidence that MOTS-c modulates oxidative stress and inflammation, with potential implications for inflammatory lung diseases [11].

MOTS-c and cardiac ischemia-reperfusion injury

In models of myocardial ischemia-reperfusion injury, MOTS-c preserved mitochondrial subpopulation bioenergetics and genome integrity, attenuating injury. The study focused on mitochondrial dysfunction as a contributor to IR injury [12].

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