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How Does Mitochondria-derived Peptide MOTS-c Affect Stress, Metabolism, and Aging?

By January 19, 2024No Comments

How Does Mitochondria-derived Peptide MOTS-c Affect Stress, Metabolism, and Aging?

MOTS-c is a recently discovered mitochondrial peptide that can change our perspectives on aging and health. With its excellent effects on aging, metabolism, and stress, MOTS-c is a promising candidate for novel and age-related illness treatments.

Read on to learn how MOTS-c can bring new possibilities to the forefront of medical study.

Exploring MOTS-c’s Crucial Role in Mitigating the Effects of Aging

What is MOTS-c?

Encoded by mitochondrial DNA, MOTS-c is a peptide consisting of 16 amino acids.

Mitochondria, the powerhouses of cells, play a pivotal role in cellular functions, ranging from energy production to stress responses, information transfer, cell death, and aging.

The relationship between mitochondrial function and various physiological processes is well-established. However, disruptions in mitochondrial activity, often linked to aging, can result in a spectrum of health issues, including:

In 2015, scientists identified MOTS-c as a novel mitochondrial-derived peptide, making it a groundbreaking discovery.

This discovery was a significant stride in understanding the molecular mechanisms through which mitochondria influence cellular functions and overall health during aging.

Despite its small size, MOTS-c has far-reaching implications. Initially recognized for its role in regulating glucose uptake, lipid metabolism, and insulin resistance, MOTS-c emerged as a key player in physiological and pathological changes associated with aging.

Notably, the expression of MOTS-c is closely linked to stress and exercise, with its levels diminishing as people age. This is why MOTS-c opened up possibilities for unraveling the connections between mitochondrial function and age-related health conditions.

What Does MOTS-c Do?

MOTS-c is a crucial regulator for maintaining energy balance within the cell, exerting its influence on amino acids, carbohydrates, and lipid metabolism.

Originating from mitochondrial DNA, MOTS-c operates within the cellular machinery to “fine-tune” metabolic processes essential for overall cellular health.

Under stress conditions, MOTS-c undergoes a notable translocation from the mitochondria to the nucleus, accompanied by increased reactive oxygen species (ROS) production.

The translocation of MOTS-c to the nucleus under stress conditions signifies its role as a responsive element in the cellular stress response network. The elevation of ROS production suggests a dynamic interplay between MOTS-c and cellular stress signaling pathways.

This interaction underscores the peptide’s involvement in orchestrating adaptive responses to stressors, contributing to the cell’s ability to maintain homeostasis.

MOTS-c in Exercise and Aging

With aging, there’s a gradual decline in mitochondrial activity, stress resilience, and physical function. Studies indicate that MOTS-c can promote healthy aging by maintaining body homeostasis, improving physical function, and mitigating aging-related pathologies.

In experiments with mice, MOTS-c demonstrated the ability to enhance physical performance across all age groups by influencing the expression of genes related to metabolism, skeletal muscle function, and stress adaptation.

Exercise triggers the expression of the natural MOTS-c in the body, forming a feedback loop involving molecules like AMPK and PGC-1α. This loop enhances muscle homeostasis, boosts exercise capacity, promotes glucose uptake, and supports stress resistance.

In addition to positively impacting muscle function, MOTS-c displays potential as a treatment for muscle atrophy and benefits those with conditions like Duchenne muscular dystrophy, one of the most debilitating forms of hereditary muscular dystrophy.

MOTS-c’s positive effects extend beyond skeletal muscle. This peptide has shown its crucial role in cardiovascular health.

MOTS-c has shown improvements in artery wall structure and vascular tone, as well as a significant decrease in vascular calcification and disordered elastic fiber count. MOTS-c may also help with endothelial dysfunction, according to a recent study.

In the heart, MOTS-c reduces the damage diabetes causes to the structure and function of the heart while also enhancing cardiac systolic and diastolic performance. Finally, MOTS-c enhances the cardiovascular benefits associated with exercise.

MOTS-c and Metabolic Homeostasis

MOTS-c has proven pivotal in maintaining metabolic homeostasis and combating insulin resistance. In experiments with mice, MOTS-c treatment reduced body weight, improved glucose utilization, and enhanced insulin sensitivity.

Notably, aged mice, typically exhibiting increased insulin resistance, regained insulin sensitivity comparable to their younger counterparts with MOTS-c treatment.

The peptide’s effects were pronounced in conditions like high-fat diet-induced obesity, where MOTS-c not only decreased obesity rates but also reduced inflammatory markers. It prevented hyperinsulinemia (high insulin in the blood) associated with high-fat diets, demonstrating its efficacy in maintaining glucose homeostasis.

However, a disparity in MOTS-c levels in different conditions remains a topic of debate. Studies have shown inconsistent MOTS-c levels in obesity, type 2 diabetes, and kidney disease, implying complex regulatory mechanisms that warrant further investigation.

MOTS-c’s influence extends to postmenopausal women, where it prevents obesity and insulin resistance. It downregulates adipogenesis-related genes, enhances lipid oxidation, and activates brown fat, showcasing its therapeutic role in postmenopausal conditions.

In diseases like gestational diabetes, MOTS-c not only improved insulin sensitivity but also reduced mortality in offspring, hinting at its broader application in metabolic disorders.

MOTS-c and Inflammation

The relationship between MOTS-c and inflammation is intricate, with the peptide showing anti-inflammatory properties through various molecular pathways.

Specifically, activating molecules such as AMPK and SIRT1 and inhibiting ROS production, MOTS-c emerges as a potential regulator of immune responses.

In sepsis, MOTS-c increased survival rates, reduced bacterial load, and modulated pro-inflammatory cytokines, highlighting its ability to balance immune responses.

In inflammatory and acute lung injury, MOTS-c exhibited anti-inflammatory effects by reducing the expression of pro-inflammatory cytokines.

MOTS-c’s impact on immune cells, including T cells and macrophages, further solidifies its anti-inflammatory role. It promotes the differentiation of regulatory T cells while inhibiting the differentiation of pro-inflammatory T helper type 1 cells. This capacity of MOTS-c holds promise in addressing autoimmune diseases like type 1 diabetes.

Moreover, MOTS-c inhibits the differentiation of bone marrow macrophages, suggesting its role in alleviating inflammation-induced bone loss and osteoporosis.

These findings underscore MOTS-c’s multifaceted role in maintaining immune balance and mitigating inflammation-associated pathologies.

Applications of MOTS-c

While further research is needed to understand the molecular mechanisms of MOTS-c fully, current findings indicate its broad therapeutic potential across various health domains:

  • Promote healthy aging
  • Enhance exercise function
  • Muscle atrophy treatment
  • Improve metabolic homeostasis
  • Cardiovascular health
  • Anti-inflammatory effects
  • Prevent osteoporosis
  • Enhance cognitive function
  • Prevent postmenopausal health problems
  • Disease-specific treatments
  • Immune modulation


MOTS-c emerges as a multifaceted peptide with immense therapeutic potential, showcasing promising applications in promoting healthy aging, enhancing exercise function, and addressing metabolic and inflammatory conditions.

However, the intricate mechanisms governing its actions, tissue specificity, and its full spectrum of applications remain areas that demand comprehensive exploration. As science delves deeper into the molecular intricacies of MOTS-c, its role in revolutionizing healthcare and aging interventions may become even more apparent.


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