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What Is MOTS-c?

MOTS-c (CAS 1457023-87-8) is a 16-amino acid mitochondrial-derived peptide (MDP) encoded within the 12S ribosomal RNA (12S rRNA) gene of the human mitochondrial genome. With a molecular weight of 2174.51 g/mol and molecular formula C₁₀₀H₁₆₂N₂₈O₂₈S₂, MOTS-c carries the sequence Met-Arg-Trp-Leu-Thr-Lys-Leu-Ser-Asp-Tyr-Asn-Leu-Leu-Ser-Arg-Leu (MRWLTKSDYNLLSRL). PubChem CID: 137506199. First identified in 2015 by Lee et al. at the University of Southern California, MOTS-c is classified as a mitokine — a mitochondrially encoded peptide that is secreted into circulation and exerts inter-organ metabolic signalling. The peptide activates AMP-activated protein kinase (AMPK) and regulates folate cycle and one-carbon metabolism under conditions of metabolic stress.

Chemical Properties

Property	Value
CAS Number	1457023-87-8
Molecular Formula	C₁₀₀H₁₆₂N₂₈O₂₈S₂
Molecular Weight	2174.51 g/mol
Residue Count	16 amino acids
Single-Letter Sequence	MRWLTKSDYNLLSRL
Three-Letter Sequence	Met-Arg-Trp-Leu-Thr-Lys-Leu-Ser-Asp-Tyr-Asn-Leu-Leu-Ser-Arg-Leu
Genomic Origin	Mitochondrial 12S rRNA gene (MT-RNR1)
Classification	Mitochondrial-derived peptide (MDP); mitokine
Primary Signalling Target	AMP-activated protein kinase (AMPK)
PubChem CID	137506199

Historical Development and Discovery

MOTS-c was first identified and characterised in 2015 by Chang Lee and colleagues at the University of Southern California Longevity Institute, published in Cell Metabolism. The discovery arose from systematic bioinformatic analysis of the human mitochondrial genome for short open reading frames (sORFs) capable of encoding small functional peptides — a search strategy motivated by growing evidence that the mitochondrial genome harboured more biological information than its characterised ribosomal RNA and protein-coding genes suggested.

The 2015 discovery positioned MOTS-c as a founding member of the mitochondrial-derived peptide (MDP) family, alongside the previously identified humanin and SHLP peptides. Unlike nuclear-encoded peptides, MOTS-c is translated within the mitochondrial matrix from a non-canonical reading frame within the 12S rRNA gene (MT-RNR1). The peptide is subsequently secreted from mitochondria, enters the cytoplasm, and under conditions of metabolic stress translocates to the nucleus where it regulates gene expression. Circulating MOTS-c levels have been reported to decline with age and increase with aerobic exercise, establishing it as an exercise-responsive mitokine of research interest in aging biology and metabolic physiology.

Chemical Architecture and Structural Features

Structural Element	Details
Sequence	MRWLTKSDYNLLSRL (Met-Arg-Trp-Leu-Thr-Lys-Leu-Ser-Asp-Tyr-Asn-Leu-Leu-Ser-Arg-Leu)
N-Terminus	Met (free amine)
C-Terminus	Leu (free carboxyl)
Disulfide Bonds	None
Aromatic Residues	Trp³, Tyr¹⁰ (contribute to UV absorbance at 280 nm)
Charged Residues	Arg², Lys⁶, Asp⁹, Arg¹⁵ (net charge: +2 at physiological pH)
Hydrophobic Residues	Trp³, Leu⁴, Leu⁷, Leu¹², Leu¹³, Leu¹⁶
Methionine Content	Met¹ (initiation codon; potential oxidation site)
Genomic Encoding	Non-canonical sORF within MT-RNR1 (12S rRNA gene)

Research Mechanisms

• AMPK Activation: MOTS-c activates AMP-activated protein kinase (AMPK), a master metabolic sensor that responds to cellular energy status (AMP:ATP ratio). AMPK activation by MOTS-c has been demonstrated in skeletal muscle and other metabolic tissues, promoting glucose uptake, fatty acid oxidation, and mitochondrial biogenesis while suppressing anabolic pathways that consume cellular energy. This AMPK-mediated mechanism positions MOTS-c as an exercise-mimetic signalling molecule at the molecular level.
• Folate Cycle and One-Carbon Metabolism Regulation: A mechanistically distinctive feature of MOTS-c is its regulation of the folate cycle — the metabolic network converting serine to glycine while producing 5,10-methylene-THF for nucleotide synthesis and methylation reactions. Under metabolic stress (e.g., glucose restriction), MOTS-c modulates folate cycle flux, producing AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), an endogenous AMPK activator. This MOTS-c → folate cycle → AICAR → AMPK axis represents a novel mitochondrial-to-nuclear metabolic signalling pathway.
• Nuclear Translocation Under Metabolic Stress: Unlike most secreted peptides that act on cell surface receptors, MOTS-c can translocate from the cytoplasm to the nucleus under conditions of metabolic stress. In the nucleus, MOTS-c associates with chromatin and modulates gene expression programmes related to stress adaptation and metabolic homeostasis, representing a non-canonical cell-autonomous mechanism distinct from its circulating mitokine role.
• Insulin Sensitisation: Research models have demonstrated MOTS-c’s capacity to improve insulin sensitivity in skeletal muscle, an effect linked to its AMPK activation and downstream modulation of glucose transporter trafficking. Insulin-resistant and high-fat diet model systems have been used to investigate MOTS-c’s effects on insulin signalling cascade components including IRS-1, PI3K, and GLUT4 translocation.
• Mitochondrial Quality Control and Mitophagy: MOTS-c has been investigated for roles in regulating mitochondrial quality control processes, including mitophagy — the selective autophagic clearance of damaged mitochondria. As a mitochondrially encoded peptide, MOTS-c may function as part of an adaptive response linking mitochondrial dysfunction to systemic metabolic signalling via its secretion and AMPK-mediated downstream effects.
• Exercise-Responsive Circulating Mitokine: Circulating plasma MOTS-c concentrations increase in response to aerobic exercise in human subjects, establishing it as an exercise-responsive mitokine. Conversely, MOTS-c levels decline with advancing age. These observations have positioned MOTS-c as a research target for understanding the molecular mechanisms linking physical activity to systemic metabolic benefits, and for investigating exercise-mimetic strategies in aging research models.

Research Areas

What Is a Mitochondrial-Derived Peptide (MDP)?

A mitochondrial-derived peptide (MDP) is a small peptide encoded within the mitochondrial genome and translated within the mitochondrial matrix. MDPs differ from nuclear-encoded peptides in that they originate from a genome with distinct codon usage and are translated by mitochondria-specific ribosomes. MOTS-c is an MDP encoded within the 12S rRNA gene — a non-canonical open reading frame within a genomic region previously characterised primarily for ribosomal RNA function. MDPs are secreted from mitochondria and can act as autocrine, paracrine, or endocrine (mitokine) signals, integrating mitochondrial status with whole-body metabolic physiology. Other characterised MDPs include humanin and the SHLP peptides.

Aging Biology and Longevity Research

MOTS-c has attracted significant interest in aging biology research following observations that circulating MOTS-c levels decline with advancing age in humans and experimental models. Age-related decline in MOTS-c has been proposed as a contributor to age-associated insulin resistance, mitochondrial dysfunction, and reduced metabolic flexibility. Administration of synthetic MOTS-c in aged animal models has been investigated for effects on physical performance, insulin sensitivity, and metabolic parameters — positioning MOTS-c as a research tool for understanding the role of mitochondrial signalling in the biology of aging and for investigating potential longevity-related mechanisms.

Exercise Physiology and Exercise-Mimetic Research

The observation that MOTS-c plasma concentrations increase following aerobic exercise in human subjects, and that MOTS-c activates AMPK — the same kinase activated by exercise-induced AMP accumulation — has positioned the peptide as a molecular mediator of exercise-responsive metabolic adaptations. Research programmes investigating exercise-mimetic compounds or the molecular mechanisms of physical activity’s metabolic benefits examine MOTS-c as a candidate effector of the exercise-to-systemic-metabolism communication axis. Studies in skeletal muscle — the primary tissue for exercise-related glucose disposal and the major site of AMPK-mediated metabolic adaptation — are central to MOTS-c exercise physiology research.

Metabolic Disease and Insulin Sensitivity Research

MOTS-c’s AMPK-activating and insulin-sensitising properties have made it a subject of research in metabolic disease models, including high-fat diet-induced insulin resistance, type 2 diabetes models, and obesity-related metabolic dysfunction experimental systems. Investigations have examined MOTS-c’s effects on glucose tolerance, skeletal muscle GLUT4 expression and translocation, hepatic glucose output, and adipose tissue insulin signalling. These studies characterise MOTS-c’s potential as a research tool for probing insulin signalling pathways and mitochondria-to-insulin-sensitivity communication in preclinical models.

Frequently Asked Questions

What is the CAS number for MOTS-c?

The CAS number for MOTS-c is 1457023-87-8. The molecular formula is C₁₀₀H₁₆₂N₂₈O₂₈S₂ and the molecular weight is 2174.51 g/mol. MOTS-c is also referenced under PubChem CID 137506199. The peptide sequence is MRWLTKSDYNLLSRL (Met-Arg-Trp-Leu-Thr-Lys-Leu-Ser-Asp-Tyr-Asn-Leu-Leu-Ser-Arg-Leu).

Where is MOTS-c encoded in the human genome?

MOTS-c is encoded within the mitochondrial genome — specifically within the MT-RNR1 gene, which encodes 12S ribosomal RNA. The MOTS-c peptide sequence is translated from a short open reading frame (sORF) within this gene using the standard mitochondrial genetic code. This non-canonical origin — a functional peptide derived from a region previously annotated solely as ribosomal RNA — was a significant discovery in the mitochondrial biology field when first reported by Lee et al. in 2015.

What is the amino acid sequence of MOTS-c?

The human MOTS-c amino acid sequence is: Met-Arg-Trp-Leu-Thr-Lys-Leu-Ser-Asp-Tyr-Asn-Leu-Leu-Ser-Arg-Leu (single-letter code: MRWLTKSDYNLLSRL). The peptide is 16 amino acids in length, with a free amine N-terminus (Met) and free carboxyl C-terminus (Leu). It contains no disulfide bonds and carries a net positive charge at physiological pH due to two Arg and one Lys residues.

How does MOTS-c activate AMPK?

MOTS-c activates AMPK through a mechanism involving regulation of the folate cycle and one-carbon metabolism. Under metabolic stress conditions, MOTS-c modulates folate cycle flux, leading to accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) — an endogenous AMPK activator. AICAR directly mimics AMP’s allosteric effect on AMPK, promoting its phosphorylation and activation. This MOTS-c → folate cycle → AICAR → AMPK axis represents a mitochondria-to-cytoplasm signalling mechanism that couples mitochondrial status to cellular energy sensing.

What is the molecular weight of MOTS-c?

The molecular weight of MOTS-c is 2174.51 g/mol. The molecular formula is C₁₀₀H₁₆₂N₂₈O₂₈S₂. The CAS number is 1457023-87-8 and the PubChem CID is 137506199. MOTS-c is a 16-amino acid linear peptide with no disulfide bonds, containing aromatic residues Trp³ and Tyr¹⁰ that contribute to UV absorbance at 280 nm.

Does MOTS-c change with exercise or aging?

Yes. Circulating plasma MOTS-c concentrations have been reported to increase with aerobic exercise in human subjects and decline with advancing age. This dual pattern — exercise-responsiveness and age-related decrease — has positioned MOTS-c as an exercise-responsive mitokine and a subject of aging biology research. The observation that a mitochondrially encoded peptide reflects both exercise status and aging parallels the known age-related decline in mitochondrial function and the established metabolic benefits of physical activity.

What distinguishes MOTS-c from other mitochondrial-derived peptides?

MOTS-c is distinguished from other mitochondrial-derived peptides (MDPs) — including humanin and the SHLP (small humanin-like peptides) family — by its genomic origin (MT-RNR1, the 12S rRNA gene, rather than the 16S rRNA gene where humanin and SHLPs are encoded), its primary signalling mechanism (AMPK activation via folate cycle regulation), and its capacity to translocate to the nucleus under metabolic stress. While humanin has been primarily studied in the context of neuroprotection and apoptosis regulation, MOTS-c’s primary research focus is on metabolic regulation, insulin sensitivity, and exercise-responsive systemic signalling.

What is the PubChem CID for MOTS-c?

The PubChem CID for MOTS-c is 137506199. The compound is catalogued under CAS 1457023-87-8 with molecular formula C₁₀₀H₁₆₂N₂₈O₂₈S₂ and molecular weight 2174.51 g/mol. MOTS-c is a 16-amino acid mitochondrial-derived peptide encoded within the MT-RNR1 (12S rRNA) gene of the human mitochondrial genome.

Published Research

• Lee C, et al. (2015). MOTS-c: A Mitochondrial-Derived Peptide Regulates Glucose and Fatty Acid Metabolism. Cell Metabolism. PMID: 25500531
• Reynolds JC, et al. (2021). MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications. PMID: 34526207
• Kim SJ, et al. (2018). Mitochondria-derived peptides in aging and healthspan. Journal of Clinical Investigation. PMID: 32060069
• Zhu HY, et al. (2021). MOTS-c improves insulin resistance and gut microbiota in obese mice. Biomolecules. PMID: 34481169
• Ming W, et al. (2020). MOTS-c modulates mitochondrial function and inflammation in sepsis. Frontiers in Physiology. PMID: 32982773
• Hu B, et al. (2023). MOTS-c administration modulates inflammatory and oxidative-stress markers in metabolic disease research models. Peptides. PMID: 36442540

Research Use Only Disclaimer

MOTS-c (CAS 1457023-87-8) is intended for laboratory research purposes by qualified professionals only. Not for human, animal, diagnostic, or therapeutic use. This compound has not been evaluated by the FDA for clinical application, is not manufactured to pharmaceutical standards, and all applicable local, state, and federal regulations governing research compounds apply.