In-Depth Analysis of MOTS-c Peptide. Image: Google

In-Depth Analysis of MOTS-c Peptide

It has been hypothesized that in reaction to metabolic stress, MOTS-c may enter the cell nucleus and regulate adaptive nuclear gene expression.


In-Depth Analysis of MOTS-c Peptide. Image: Google

There are 37 known genes in mitochondrial DNA (mtDNA) that code for components of the electron transport chain (ETC) complexes; these genes include 2 ribosomal RNAs (rRNAs), around 22 transfer RNAs (tRNAs), and 13 polypeptide components. New studies have suggested that rRNA regions include tiny open reading frames (ORFs) that may be translated into biologically active short peptides called mitochondrial-derived peptides (MDPs). Research suggests the mitochondrial DNA encodes a peptide called MOTS-c, composed of 16 amino acids derived from cells’ 12S rRNA region of mtDNA.

It has been hypothesized that in reaction to metabolic stress, MOTS-c may enter the cell nucleus and regulate adaptive nuclear gene expression. This proposed characteristic is believed to enable the peptide to improve metabolic stress resistance by boosting mitochondrial genome activity, which may promote mitochondrial biogenesis and expand the number of mitochondrial genes. By blocking the methionine-folate cycle, MOTS-c has been proposed to decrease purine synthesis, raise PCG-1α, an important regulator of energy metabolism, and cause AICAR, which may activate AMPK, to accumulate. In response to low energy levels, AMPK initiates catabolic processes to generate ATP, acting as an energy sensor that controls the ratio of AMP to ATP.

In addition, previous research has purported that MOTS-c may improve GLUT4 uptake in muscle tissue and decrease insulin resistance. Researchers speculate the primary function of this peptide may be to aid in weight management by controlling the metabolism of fat and muscle and increasing energy levels to help cells survive in harsh environments. 

The prospective research applications of MOTS-c have been the subject of several studies spanning a wide range of areas:


Scientists theorize that possible new approaches in the context of metabolic diseases may lie in MOTS-c’s potential to improve glucose metabolism and insulin sensitivity. As suggested by research, it may help reduce the symptoms of diseases like obesity and type 2 diabetes by addressing possible root causes.


Mitochondrial dysfunction and oxidative stress are often associated with age-related diseases. Some speculate that MOTS-c may help with age-related issues, such as cardiovascular disease and neurological illnesses, by maintaining mitochondrial integrity.


Scientific investigations suggest that MOTS-c may improve physical activity performance and aid recovery by improving muscular function and decreasing the oxidative stress caused by intense activity. 


Hypotheses have been formed about MOTS-c’s potential to provide neuroprotection. Potentially relevant to neurodegenerative diseases like Alzheimer’s, MOTS-c suggests promise in protecting neurons from damage by controlling cellular stress responses and maintaining mitochondrial function.


Many disorders share the symptoms of chronic inflammation. Data suggests that MOTS-c may have anti-inflammatory effects by modulating inflammatory responses, making it a promising research candidate in the context of diseases defined by chronic inflammation.

MOTS-c Peptide Overview

Although mitochondria’s function as organelles is considered to be \well-established, their importance as signaling units is now beginning to be acknowledged. There may be further short open reading frames (sORFs) in the mitochondrial DNA (mtDNA) due to the finding of the Humanin signaling peptide’s encoding in mtDNA. Here, researchers speculate the discovery of a single open reading frame (sORF) in the mitochondrial 12S rRNA that encodes a peptide of 16 amino acids called MOTS-c. Findings imply that MOTS-c may be critical for maintaining metabolic homeostasis and insulin sensitivity. It seems that skeletal muscle is its principal target. This tissue inhibits the folate cycle and the related de novo purine production, activating AMPK.

Mice given MOTS-c appeared to exhibit protection against insulin resistance due to aging, dietary factors, and obesity caused by dietary factors. The results suggest that mitochondria could actively use peptides encoded in their DNA to control metabolic balance on cellular and organismal scales.

MOTS-c Peptide and Metabolism

MOTS-c is theorized to be an important regulator of skeletal muscle metabolism since it may act mostly in this tissue. Using the intricate folate-purine-AMPK pathway, MOTS-c is proposed to affect metabolism. The folate cycle and its accompanying de novo purine production are speculated to be inhibited in this pathway, which may later activate AMP-activated protein kinase (AMPK). By calculating the levels of adenosine triphosphate (ATP) relative to adenosine monophosphate (AMP), AMPK serves as an essential cellular energy sensor. When there is a need for extra energy, the activation of AMPK initiates catabolic activities that produce more ATP.

MOTS-c Peptide and Insulin Sensitivity

MOTS-c is assumed to be a paramount mediator in maintaining metabolic homeostasis and insulin sensitivity. Investigations purport that the mitochondria and the cell’s nucleus may interact with the help of this signaling peptide. In response to metabolic stress or other disturbances, MOTS-c is hypothesized to enter the nucleus and regulate gene expression in adaptive metabolism. Cells rely on this nucleus-mitochondrial cooperation to better adapt to fluctuating energy needs.

MOTS-c Peptide and Obesity

Researchers speculate one of its most interesting features is that MOTS-c may protect against nutrient- and age-related physiological ailments. Data from studies indicates that MOTS-c may ward against age-related insulin resistance, a hallmark of cell aging and a risk factor for metabolic diseases, including type 2 diabetes. Potentially aiding in the context of insulin resistance and obesity-related diseases, MOTS-c is theorized to maintain insulin sensitivity while encouraging a high functioning metabolism.


Sarcopenia and muscular dysfunction are metabolic diseases that are often linked with obesity and type 2 diabetes. Studies suggest that the mitochondria-derived peptide MOTS-c may be involved in maintaining metabolic balance, and it may act as a systemic hormone. Not much is known about how MOTS-c may affect muscle atrophy, while it is speculated that it might increase insulin sensitivity in skeletal muscle. One protein that may contribute to insulin resistance-induced muscle atrophy is myostatin, which adversely controls skeletal muscle mass.

Surprisingly, research hinted that myostatin levels appeared to be inversely related to MOTS-c levels in the blood. In addition, the researchers speculated that differentiated C2C12 myotubes seemed protected against palmitic acid-induced muscle atrophy by using MOTS-c. Findings implied plasma myostatin levels seemed lower in diet-induced obese mice after the presentation of MOTS-c. This result occurs, so researchers speculate, because MOTS-c has been hypothesized to increase AKT phosphorylation, suppressing FOXO1, a key transcription factor that may activate myostatin and other genes linked to muscle atrophy. Preliminary studies have led researchers to assume MOTS-c may modulate AKT phosphorylation via increasing mTORC2 activity and decreasing PTEN. Moving upstream further, MOTS-c may also inhibit PTEN by increasing CK2 activity. Click here to be redirected to the Core Peptides website for more educational peptide articles.

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