MOTS-c and SS-31 both get called “mitochondrial peptides,” but the label hides some big differences. MOTS-c is a 16-residue peptide encoded within mitochondrial DNA and studied for its role in cellular signaling. SS-31 is a synthetic four-residue peptide that binds cardiolipin in the inner mitochondrial membrane. We’ll compare their structures, molecular interactions and findings from cell and animal experiments.
Key findings
- Lee 2015 found MOTS-c hiding in a short reading frame of the mitochondrial 12S rRNA gene. 16 amino acids.
- In Lee’s cell experiments, MOTS-c altered folate and purine metabolism and activated AMPK.
- Stress the cell and MOTS-c heads for the nucleus, where it shifts gene expression (Kim 2018). That needed AMPK.
- Birk’s group (2013, 2014) showed SS-31 grabs cardiolipin and pretty much ignores membranes without it.
Where each one comes from
Here’s the thing most people miss. Mitochondria carry their own little genome. For years the working assumption was that it held a few respiratory chain genes plus some RNAs, and that was that. Humanin broke the assumption. If one signaling peptide was tucked in there, why not more?
Lee, Cohen and colleagues identified a short open reading frame within the 12S rRNA gene. It encodes MOTS-c, short for mitochondrial open reading frame of the 12S rRNA type-c [1]. That origin distinguishes it from a peptide designed in the lab.
SS-31 came out of Hazel Szeto’s lab and was designed on purpose. Its sequence is D-Arg-dimethylTyr-Lys-Phe-NH2 [4], and the D-arginine and dimethyltyrosine aren’t decorations. They’re there for stability and to help it reach the inner membrane.
How MOTS-c works (as far as anyone knows)
The original paper examined MOTS-c in cultured cells and mouse skeletal muscle [1]. In the cell experiments, the researchers reported reduced folate-cycle and purine-synthesis activity, along with AMPK activation. In the high-fat-diet mouse experiments, the MOTS-c group had less weight gain and higher insulin sensitivity than controls.
Then it got stranger. In 2018 Kim and colleagues showed that when cells were starved of glucose or otherwise stressed, MOTS-c went into the nucleus [2]. Once there, it regulated a wide set of genes, including ones with antioxidant response elements, and it interacted with stress-responsive transcription factors. This depended on AMPK. A mitochondrial gene product directly steering nuclear genes is not something textbooks had room for.
Reynolds and colleagues assessed physical performance in young, middle-aged and old mice in 2021 [3]. They reported higher measured physical capacity in the MOTS-c mouse groups than in controls. The paper also included a late-life mouse experiment beginning at 23.5 months of age.
Our MOTS-c compound page has the basic identifiers. AMPK keeps showing up in mitochondrial metabolism papers, by the way; it also sits in the middle of the BAM15 and SLU-PP-332 research.
How SS-31 works
Cardiolipin is a weird lipid. It’s found almost only in the inner mitochondrial membrane, it helps hold the cristae folds together, and it keeps the respiratory complexes packed tight. When it gets oxidized, things fall apart.
Birk and colleagues used a fluorescent version of SS-31 to show high-affinity binding to cardiolipin [5]. In biochemical assays, the SS-31 and cardiolipin complex inhibited cytochrome c peroxidase activity. In a rat renal ischemia model, the SS-31 group showed more intact cristae, less mitochondrial swelling and faster ATP recovery after blood flow returned than controls.
The same lab came back in 2014 with liposomes, bicelles and NMR [4]. Plain phosphatidylcholine vesicles? SS-31 didn’t care. Spike in cardiolipin and suddenly it binds, about one SS-31 per cardiolipin, aromatic rings buried deep in the bilayer. Fresh mitochondria given SS-31 showed faster state 3 respiration and squeezed more ATP out of each unit of oxygen.
MOTS-c research centers on metabolic signaling and nuclear gene regulation. The SS-31 studies discussed here examined cardiolipin binding and mitochondrial membrane interactions.
Comparing experimental models
The studies above used different experimental systems. MOTS-c work included cultured cells and mice; the SS-31 papers used lipid vesicles, isolated mitochondria and a rat ischemia model. Those differences matter when comparing the measurements.
Quick comparison
| MOTS-c | SS-31 (elamipretide) | |
|---|---|---|
| Length | 16 amino acids | 4 amino acids |
| Origin | Encoded in mitochondrial DNA (12S rRNA) | Synthetic, designed in the lab |
| Main target | Folate cycle, AMPK, nuclear gene expression | Cardiolipin in the inner mitochondrial membrane |
| Best-studied models | Mouse metabolism and physical capacity | Lipid vesicles, isolated mitochondria and rat renal ischemia |
| Selected measurements | AMPK signaling, nuclear localization and gene expression | Cardiolipin binding, membrane structure and mitochondrial respiration |
Limits of the comparison
The studies cited here examined MOTS-c and SS-31 separately. They do not establish how the peptides interact in the same experimental system. Sharing a connection to mitochondria isn’t evidence of a combined effect.
References
- Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443 to 454. PMID 25738459
- Kim KH, Son JM, Benayoun BA, Lee C. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. 2018. PMID 29983246
- Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12(1):470. PMID 33473109
- Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol. 2014;171(8):2017 to 2028. PMID 24134698
- Birk AV, Liu S, Soong Y, et al. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol. 2013;24(8):1250 to 1261. PMID 23813215
- Karaa A, Bertini E, Carelli V, et al. Efficacy and safety of elamipretide in individuals with primary mitochondrial myopathy: the MMPOWER-3 randomized clinical trial. Neurology. 2023;101(3):e238 to e252. PMID 37268435
- Zhao C, Zhuang X, Gao J. Elamipretide: the first cardiolipin-directed mitochondrial therapeutic for Barth syndrome approved under accelerated approval. Drug Discov Ther. 2025;19(6):435 to 436. PMID 41260682
Disclaimer: This content is intended for research purposes only and is not meant to constitute medical advice.
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