Long known as the cell’s powerhouse, mitochondria play a pivotal role in the science of disease, aging, and metabolic health.

In any meaningful conversation about mitochondrial function, peptides like MOTS-c and SS-31 naturally come into focus, offering distinct insights into how we might influence cellular performance at its core.

Among them, MOTS-c, a naturally occurring peptide encoded by mitochondrial DNA, and SS-31, a synthetic analogue engineered to stabilise mitochondrial membranes, have captured the attention of researchers worldwide. 

Both hold remarkable promise in reshaping how we approach mitochondrial dysfunction, whether in age-related decline or chronic disease.

Their mechanisms differ; MOTS-c modulates metabolism and cellular stress responses, while SS-31 works by binding to cardiolipin to mitigate oxidative damage. 

Comparing their mechanisms and potential applications reveals two very different paths toward mitochondrial support, one grounded in nature, the other in design.

We tend to say MOTS-c is the mitochondrial software upgrade and SS-31 is the mitochondrial hardware upgrade.

What are natural MOTS-c Peptide and synthetic SS-31 Peptide?

MOTS-c

MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c) is a naturally occurring mitochondrial peptide, encoded by mitochondrial DNA. 

This distinguishes MOTS-c peptide from most other peptides, as they are typically encoded in the nucleus of cells.

MOTS-c Peptide plays a key regulatory role in metabolic homeostasis by helping cells to adapt to stress by enhancing fat oxidation, glucose metabolism and insulin sensitivity.

MOTS-c is also known to translocate to the nucleus when cells are under metabolic stress. 

Here, it regulates the expression of genes that contribute to inflammation, cellular repair and stress resistance. 

Preclinical studies of MOTS-c suggest that it may also be a potential candidate for anti-aging and metabolic therapeutics due to its other effects on age-related resilience and its potential to improve exercise capacity. 

As it is derived naturally, has hormone-like systemic effects and a direct involvement in mitochondrial function, MOTS-c is a great target for conditions like type 2 diabetes, cardiovascular disease, age-related decline and obesity. 

For example, insulin resistance and MOTS-c were investigated by Lee et al. 

Older mice with insulin resistance were given MOTS-c over a 7 day period and were found to have improved their insulin sensitivity to the point where it was now the same as the younger mice. 

This preclinical study and multiple others are great models of the capabilities that MOTS-c has in treating these types of conditions in humans.

                                                                  MOTS-c 15mg Peptide Pen 

Synthetic SS-31 Peptide

SS-31, otherwise known as Elamipretide, is a synthetic tetrapeptide unlike the naturally occurring MOTS-c. 

SS-3 was created to protect and target the inner mitochondrial membrane by binding to a critical phospholipid, cardiolipin. 

This lipid is essential to the upholding of mitochondrial structure and the function of the electron transport chain.

SS-31 works directly within mitochondria unlike MOTS-c. 

Its main role is to stabilise energy production from the mitochondria, prevent mitochondrial-driven cell damage and reduce reactive oxidative species (ROS).

These roles support the process of ATP synthesis, reducing oxidative stress and protecting tissues that are under ischaemic or metabolic stress.

SS-31 has been investigated in preclinical and clinical studies for its therapeutic ability to treat conditions that involve mitochondrial dysfunction as one of their root causes. 

Types of conditions include:

• Kidney Injury
• Heart Failure
• Mitochondrial myopathies
• Age-related macular degeneration

In the context of kidney damage linked to high-fat diets, SS-31 has demonstrated an ability to significantly reduce inflammation in the glomeruli by as much as 50%. 

This points to its potential in preserving kidney function under metabolic strain, particularly where traditional interventions may fall short.

With its ability to improve cellular energy dynamics and stabilise mitochondrial activity, SS-31 has proven to be a mitochondrial-targeted therapeutic agent worth exploring more in both acute and chronic disease.

                                                                    SS-31 30mg Peptide Pen

Why Mitochondrial Peptides?

Mitochondria are more than just ‘powerhouses’. 

Other than producing adenosine triphosphate (ATP), our body’s primary energy store, the mitochondria is involved in many bodily processes such as immune signalling, cell survival and death (apoptosis) and the metabolism of carbohydrates, fats and amino acids. 

It has been found that when damaged, they contribute to the development of metabolic diseases like diabetes, neurodegenerative diseases, cardiovascular disease, cancer and even aging.

The discovery of short open reading frames (sORFs) in mitochondrial DNA, like humanin (the first known member of this class of peptides) and MOTS-c, showed that mitochondria have more roles than previously known. 

Their discovery showed that mitochondria can synthesise signalling peptides that have systemic effects.

This class of peptide acts like a hormone. It circulates in the blood and affects metabolism, inflammation, gene expression and stress resistance.

Unlike most drugs, mitochondrial peptides have the potential to target the root cause of a disease instead of just treating the symptoms. 

Other potential benefits of taking mitochondrial peptides include:

• Potential to slow down neurodegeneration and cognitive decline.
• Preservation of mitochondria in heart muscle during aging or ischemia.
• Enhancement of vascular function and blood flow.
• Increase insulin sensitivity (as seen with MOTS-c).
• They could help to regulate weight and prevent obesity.
• Promote cellular resilience to stress and aging.

Comparing MOTS-c and SS-31

Despite both MOTS-c and SS-31 being mitochondrial peptides, they both differ significantly in terms of their structure, mechanism of action and their therapeutic focus.

It is essential to understand these differences in order to decide which mitochondrial peptide would be more suitable for addressing specific aspects of mitochondrial dysfunction, metabolic imbalance and aging.

Clinical Positioning and Approval Status

SS-31 (Elamipretide) has progressed through multiple Phase 2 and 3 clinical trials, primarily targeting mitochondrial diseases, heart failure, and age-related macular degeneration (AMD). 

Though it is not yet FDA-approved for general usage, it has been granted orphan drug status allowing it to be used to treat certain rare conditions like Duchenne muscular dystrophy and Friedreich Ataxia.

MOTS-c remains a researched peptide with promising preclinical results in metabolic health, aging, and exercise physiology. Human trials are starting, but it is currently not FDA-approved.

Frequently Asked Questions (FAQs)

What’s the main difference between MOTS-c and SS-31?

MOTS-c is a naturally occurring mitochondrial peptide encoded by mitochondrial DNA. It functions as a metabolic regulator, influencing gene expression and improving stress resilience. SS-31 (Elamipretide) is a synthetic tetrapeptide that targets mitochondria directly, stabilising energy production and protecting cells against oxidative damage.

Which peptide is better for improving mitochondrial function?

It depends on the context. MOTS-c supports long-term metabolic health and cellular adaptability, making it more suitable for chronic conditions, aging, and metabolic dysfunction. SS-31 offers direct mitochondrial protection and is better suited for acute
injuries, organ-specific mitochondrial dysfunction, or age-related mitochondrial decline.

Is one more natural or safer than the other?

MOTS-c is naturally produced in the body and mimics internal biological processes, which may make it more biocompatible. SS-31 is synthetic but has undergone multiple clinical trials and has shown a good safety profile so far. Long-term human safety data is still developing for both.

Can MOTS-c and SS-31 be used together?

There’s no widely published data yet on combining them, but theoretically, they could be complementary as MOTS-c is used for regulating systemic metabolic health, and SS-31 is for protecting mitochondria directly under acute stress or damage. Always consult a qualified medical professional for combined usage.

Which has more human clinical data?

SS-31 has been tested in several human clinical trials, particularly for heart and eye diseases. MOTS-c has more preclinical data in animals, though human studies are beginning to emerge.

Which one is better for anti-aging?

Both show anti-aging potential but through different mechanisms. MOTS-c regulates genes linked to longevity, metabolism, and exercise capacity. SS-31 improves mitochondrial function in aging tissues and may help prevent age-related degeneration.

What should I look for when purchasing MOTS-c or SS-31?

When sourcing these peptides, it’s essential to look for:

• Third-party testing for purity and consistency
• U.S.-based manufacturing standards
• Reliable delivery

DN Lab Research meets all these criteria, offering high-quality peptides backed by transparency, compliance, and efficient service.

Which conditions are they best suited for?

MOTS-c is more suited to conditions like metabolic syndrome, insulin resistance, obesity and age-related fatigue. Whereas SS-31 is more suited to conditions like heart failure, kidney injury, neurodegeneration, mitochondrial myopathies, and age-related macular degeneration (AMD). However, always consult a qualified medical professional for personalised treatment.

What to Know Before You Order

MOTS-c and SS-31 represent a new insight into targeting mitochondrial health, offering promising options for treating aging, cellular resilience and metabolic dysfunction.

The best choice depends on individual goals, tolerability, comorbidities, and access. 

Need help choosing the right peptide for your goals? 

Schedule a consultation with one of our dedicated peptide research specialised to get personalised guidance and support. 

Written by Elizabeth Sogeke, BSc Genetics, MPH

Elizabeth is a science and medical writer with a background in Genetics and Public Health. She holds a BSc in Genetics and a Master’s in Public Health (MPH), with a focus on mitochondrial science, metabolic health, and healthy aging. Over the past several years, she has worked with leading peptide research laboratories and functional medicine clinics, creating trusted, clinically-informed content that bridges the latest developments in peptide and longevity research with real-world applications.