MOTS-c vs. SS-31

Happy Monday!

Today, I’m answering a viewer question that I get all the time regarding mitochondrial health:

It’s a fantastic question because mitochondria are literally the powerhouses of our cells—so if your mitochondria aren’t thriving, you definitely aren’t thriving.

Let’s dig in!

First, Why Should You Even Care About Mitochondrial Health?

Mitochondria produce ATP, which is essentially your body’s energy currency. Healthy mitochondria mean:

• More energy

• Better metabolism

• Enhanced longevity

• Less inflammation and oxidative stress

Poor mitochondrial health contributes directly to aging, fatigue, brain fog, and chronic disease—everything from diabetes to Alzheimer’s.

This is exactly why peptides targeting mitochondria have become game-changers.

And this brings us to two of the absolute best mitochondrial peptides available today: MOTS-c and SS-31.

What is MOTS-c?

MOTS-c is a 16-amino acid peptide naturally encoded within our mitochondria.

It essentially acts as a signaling molecule, a “mitokine,” which means your mitochondria literally produce MOTS-c to signal cells throughout your body to adapt and become stronger.

Think of MOTS-c as your internal metabolic personal trainer.

It activates a crucial metabolic switch called AMPK, the master regulator of energy metabolism. AMPK activation results in:

• Better insulin sensitivity (great for blood sugar control)

• Increased fat burning (hello, leaner body composition!)

• Improved mitochondrial biogenesis (creating new, stronger mitochondria)

• Enhanced exercise capacity and endurance

MOTS-c is especially powerful for metabolic dysfunction, obesity, diabetes, and age-related physical decline.

Animal studies even show it improves memory, protects bones, and boosts exercise performance, giving it a reputation as an “exercise mimetic.”

What is SS-31 (Elamipretide)?

Unlike MOTS-c, SS-31 is a synthetic tetrapeptide designed specifically to protect mitochondria from the inside out.

Its main action is directly targeting and protecting cardiolipin, a crucial mitochondrial lipid.

SS-31 stabilizes mitochondria, reduces oxidative damage, and helps mitochondria produce ATP more efficiently.

If MOTS-c is your metabolic coach, SS-31 is your mitochondrial bodyguard.

SS-31 works by:

• Immediately reducing oxidative stress inside mitochondria

• Preserving mitochondrial structure and integrity

• Preventing cell death by stabilizing mitochondrial membranes

• Improving organ function (especially beneficial for the heart, brain, kidneys, and muscles)

Clinical trials have shown SS-31 is particularly helpful for genetic mitochondrial diseases like Barth syndrome, and it’s also demonstrated benefits in heart conditions and potentially age-related vision loss (macular degeneration).

Similarities Between MOTS-c and SS-31

Both MOTS-c and SS-31 ultimately share the same goal—better mitochondrial health and function. Both:

• Enhance mitochondrial efficiency

• Reduce oxidative stress

• Improve energy production and resilience against cellular stress

In short, both improve how your mitochondria function—just in very different ways.

How MOTS-c and SS-31 Are Different

The key differences are in their mechanism, timing, and ideal use cases:

• MOTS-c works indirectly by activating metabolic pathways (AMPK) and gene expression. It’s like enhancing your mitochondrial health through “software updates,” improving how your entire body uses energy and responds to stress.

• SS-31 directly protects mitochondrial membranes and reduces immediate stress and damage. It’s the “hardware upgrade”—immediately stabilizing and protecting mitochondria, especially in scenarios of acute injury or ongoing mitochondrial stress.

Think of it like this:

• MOTS-c is like upgrading your body’s internal metabolic settings and software.

• SS-31 is about giving your mitochondria immediate protection and upgrading their hardware.

When Should You Use MOTS-c vs SS-31?

Choosing between MOTS-c and SS-31 really depends on your specific circumstances and goals. Here’s a simplified breakdown:

Use MOTS-c first if you’re dealing with:

• Chronic metabolic issues like insulin resistance, obesity, pre-diabetes, or metabolic syndrome.

• Age-related physical decline (less energy, muscle loss, decreased endurance).

• Desire to enhance metabolic health and longevity over the long-term.

• You want the equivalent of a cellular-level workout without having to hit the gym (though you should definitely still exercise!).

MOTS-c is all about preventive, systemic, and long-term metabolic upgrades.

Use SS-31 first if you’re dealing with:

• Acute mitochondrial stress or injury (like after a heart attack, traumatic injury, or intense oxidative stress).

• Mitochondrial-related diseases (genetic mitochondrial conditions, neurodegenerative diseases like Alzheimer’s, Parkinson’s, and heart failure).

• Situations where immediate mitochondrial protection and quick stabilization are critical.

• A known issue with specific organ function that heavily depends on mitochondrial health (especially the heart, kidneys, or brain).

SS-31 is best suited for acute, targeted mitochondrial rescue.

Which Should You Start With? (My Practical Advice)

Here’s my personal recommendation based on everything we currently know and see clinically:

General anti-aging and metabolic optimization for generally healthy people:

Start with MOTS-c. It’s your “baseline” peptide to significantly improve metabolism, insulin sensitivity, and mitochondrial biogenesis. Think of MOTS-c as a “metabolic tune-up” to lay a solid foundation for mitochondrial health long-term.

If you need help with immediate or specific mitochondrial issues:

Start with SS-31. If you have acute mitochondrial stress, organ dysfunction, or a mitochondrial-related condition (cardiac, neurodegenerative, muscular), SS-31 will offer more immediate support, directly protecting mitochondria from further damage.

Combination Therapy (The Best of Both Worlds):

Honestly, a combination or sequential therapy of MOTS-c and SS-31 could offer incredible synergy.

The optimal solution for comprehensive mitochondrial rejuvenation is to use SS-31 initially for rapid mitochondrial protection and then introduce MOTS-c for longer-term systemic metabolic enhancement.

I personally cycle through both of them at various points of the year to all the benefits.

However, do NOT fret about taking one or the other first.

At the end of the day, the most important thing is to take them.

For most of my audience (those seeking long-term metabolic health, fat loss, energy, and anti-aging), MOTS-c first is a fine entry point.

Once your metabolism is humming, layering in SS-31 if additional organ-specific mitochondrial support is needed makes sense.

If you are severely inflamed and have various chronic health issues, it’s better to take SS-31 first to help with the “hardware upgrade”.

Then you can come in with MOTS-c following the SS-31 to ensure your new hardware gets the best “software upgrade.”

Bottom Line

• MOTS-c: For metabolic improvement, longevity, systemic mitochondrial enhancement—great first choice for general wellness and long-term health.

• SS-31: Immediate mitochondrial protection for acute injuries, organ-specific support, or severe mitochondrial dysfunction.

Ultimately, the decision depends on your specific scenario, but hopefully, this clarifies exactly how to think about MOTS-c vs SS-31.

And if you need help with dosing, don’t forget to check out the new peptide cheat sheet here: https://drive.google.com/file/d/1xYDj0XhSrrMIyCEl7RWGfZ8WNv_q87Nz/view?usp=sharing

Best,

Hunter Williams