Journal September 16, 2026 5 min read

What is MOTS-c?

MOTS-c is a mitochondrial-derived peptide encoded within the 12S rRNA region of mitochondrial DNA. This article summarises its discovery, proposed mechanisms, and the preclinical and clinical research surrounding it.

peptides-pro Editorial

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a mitochondrial-derived peptide (MDP) encoded within the 12S rRNA region of mitochondrial DNA [1][11]. It is also referred to as a mitochondrial-encoded host defense peptide (HDP) and a mitokine [1][11]. The peptide sequence is Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg [4]. Its molecular formula and molecular weight are not provided in the evidence base.

Research on MOTS-c centres on its role as a mitochondrial-encoded peptide with direct antibacterial and immunomodulatory functions, and its involvement in metabolic and inflammatory pathways [1][2].

Research Studies

MOTS-c and host defense peptide activity

A study identified MOTS-c as a mitochondrial-encoded host defense peptide with direct antibacterial and immunomodulatory functions [1]. The peptide was described as amphipathic and cationic, consistent with the chemistry of known HDPs [1]. The study demonstrated that MOTS-c targeted Escherichia coli [1]. This work was conducted in vitro and in animal models; no human data were reported.

MOTS-c and inflammasome activation in a diabetic rat model

In a high-fat diet and streptozotocin-induced type 2 diabetes mellitus (T2DM) rat model, MOTS-c treatment significantly reduced fasting blood glucose and circulating C-reactive protein levels, while selectively modulating plasma inflammatory markers [2]. The study investigated the effects of MOTS-c on NLRP3 inflammasome activity in systemic and cardiac tissues [2]. This evidence is animal-only.

MOTS-c and Hashimoto's thyroiditis in human patients

A cross-sectional study compared patients diagnosed with Hashimoto's thyroiditis (HT) (n = 90) with age- and sex-matched healthy controls [3]. The study aimed to investigate the association between circulating MOTS-c levels and HT, and to explore its potential role in thyroid autoimmunity and metabolic regulation [3]. Reduced circulating MOTS-c levels were observed in HT patients, reflecting integrated autoimmune and metabolic dysregulation [3]. This is human observational data; causality cannot be inferred.

R13A-MOTS-c and radiation-induced lung injury

To overcome poor membrane permeability due to high polarity, an engineered variant, R13A-MOTS-c, was created by substituting the polar arginine at position 13 with alanine in the wild-type peptide [4]. This modification increased the peptide's hydrophobicity index from -0.938 to -0.544, improving cellular uptake [4]. Functional uptake assays, including competition with canonical LAT1 substrates (leucine, BCH) and LAT1 knockdown experiments, confirmed that R13A-MOTS-c enters cells via LAT1-mediated delivery [4]. In a model of radiation-induced lung injury, R13A-MOTS-c attenuated injury via Nrf2 activation and mitochondrial protection [4]. This evidence is from in vitro and animal studies.

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

A study investigated the expression of humanin (HN) and MOTS-c in atrial fibrillation (AF) patients and evaluated their therapeutic potential in an AngII-induced mouse model and primary cardiac cells [5]. HN and MOTS-c expression in human atrial tissues was analysed using public GEO data, immunohistochemistry, and immunofluorescence, and plasma levels were measured [5]. The study found that humanin and MOTS-c attenuated atrial fibrillation by suppressing fibrosis and mitochondrial dysfunction [5]. This includes human observational data and animal model evidence.

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

A cross-sectional study enrolled 72 acute myocardial infarction (AMI) patients undergoing percutaneous coronary intervention (PCI), divided into MIRI (n = 34) and non-MIRI (n = 38) groups [6]. The study investigated the relationship between serum MOTS-c levels and myocardial ischemia-reperfusion injury (MIRI) [6]. MOTS-c levels were measured in peripheral serum and intracoronary blood [6]. This is human observational data; no interventional effect is reported.

MOTS-c and polycystic ovary syndrome in adolescents

A study investigated differences in MOTS-c levels between adolescents diagnosed with polycystic ovary syndrome (PCOS) and those without PCOS, as well as associations with metabolic parameters [7]. The association between the MOTS-c gene polymorphism m.1382A>C and serum MOTS-c levels was also evaluated [7]. The m.1382A>C polymorphism has been linked to an increased risk of type 2 diabetes in men [7]. This is human observational data.

MOTS-c and renal transplantation under different anesthetic techniques

A prospective controlled study aims to compare the effects of sevoflurane general anesthesia (SGA) and combined spinal-epidural anesthesia on ferroptosis, humanin and MOTS-c levels in renal transplantation [8]. The study rationale notes that ischemia-reperfusion injury may adversely affect graft function and long-term outcomes, and that humanin and MOTS-c are thought to exert protective effects against oxidative stress [8]. This is an ongoing clinical trial; results are not yet available.

MOTS-c in sepsis-induced cardiomyopathy

A review discusses MOTS-c in sepsis-induced cardiomyopathy (SICM), a cardiac complication of sepsis characterized by inflammatory dysregulation, mitochondrial dysfunction, metabolic disturbance, and changes in the myocardial microenvironment [9]. The review covers mechanisms and translational potential [9]. This is a review article; no new primary data are presented.

MOTS-c and human mesenchymal stromal cells

A study investigated the effects of MOTS-c on human mesenchymal stromal cells (MSCs), which possess therapeutic potential largely reliant on intact mitochondrial function to maintain reparative function [10]. Obesity compromises MSC metabolism and reparative capacity [10]. The study found that MOTS-c activates metabolic signaling but blunts reparative function in human MSCs [10]. This is in vitro human cell data.

MOTS-c and inflammatory lung diseases

A review discusses MOTS-c as a secreted mitochondrial microprotein (mitokine) encoded within the 12S rRNA gene that exerts intracrine, paracrine, and endocrine effects across multiple tissues [11]. Although initially described as a regulator of metabolic homeostasis, growing evidence indicates that MOTS-c also modulates oxidative stress and inflammation, suggesting potential as a treatment for inflammatory lung diseases [11]. This is a review article.

MOTS-c and cardiac ischemia-reperfusion injury

A study investigated MOTS-c in myocardial ischemia-reperfusion (IR) injury, which involves impaired bioenergetics, oxidative stress, and disruption of mitochondrial homeostasis [12]. MOTS-c, encoded within the 12S rRNA region of mtDNA, has been implicated in preserving mitochondrial subpopulation bioenergetics and genome integrity to attenuate cardiac IR injury [12]. This evidence is from animal models.

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