MOTS-c in Kidney Failure: 160 Adults, Wasting Not Linked
A group at Karolinska Institutet measured mitochondrial-derived peptides in the serum of 160 adults with kidney failure and 80 controls, alongside markers of glycoxidative stress. The paper appeared in Antioxidants on 30 July 2026.
Two things came out of it. The peptide tracked one set of markers closely. It tracked nutritional status not at all.
The second finding is the more useful one, because it is a negative, and negatives are what tell you what a measurement is not.
A framing note. This is an observational study in patients. Peptra Labs supplies MOTS-c as a reference material for laboratory research only, and nothing below is guidance about human use or about managing kidney disease.
What was measured
The cohort was 160 adults with kidney failure who were undergoing living-donor kidney transplantation, compared against 80 controls. Serum was assayed by ELISA.
Three families of markers were measured. Advanced glycation end products, the compounds that accumulate when sugars react non-enzymatically with proteins. The soluble receptor isoforms that bind them, reported as sRAGE, esRAGE and cRAGE. And the mitochondrial-derived peptides, of which the two measured here are humanin and MOTS-c.
Mitochondrial-derived peptides are short sequences encoded within mitochondrial DNA rather than in the nucleus, which is what makes them unusual. Their circulating concentration is treated as a readout of mitochondrial stress signalling, and the premise of this paper is that the glycation axis and the mitochondrial axis might be connected.
What differed between the groups
| Serum marker | In kidney failure versus controls |
|---|---|
| Advanced glycation end products | higher |
| esRAGE | higher |
| AGEs to sRAGE ratio | lower |
| Mitochondrial-derived peptides | reduced |
The authors report that pattern as increased glycoxidative stress accompanied by reduced mitochondrial-derived peptides.
The ratio deserves a note. AGEs divided by soluble receptor is used as a rough index of how much glycation burden is left unbuffered, because the soluble receptor forms act as decoys that mop up ligand before it reaches the membrane-bound receptor. A lower ratio in this cohort therefore does not read as less glycation, since absolute AGEs were higher; it reads as a shift in the balance between ligand and decoy.
Where MOTS-c sits in the correlations
In the unadjusted associations, the authors report that advanced glycation end products correlated positively with sRAGE, cRAGE and humanin, while MOTS-c was inversely associated with AGEs and with the AGEs to sRAGE ratio.
That split between the two mitochondrial-derived peptides is the interesting part. Humanin moved with the glycation markers. MOTS-c moved against them.
In multivariable analysis the split held. Humanin remained independently associated with AGEs, with sRAGE and with the ratio. MOTS-c retained only the inverse association with the ratio.
So the two peptides that come from the same genome, are measured on the same plate and are usually spoken of as one class behave differently against the same set of markers. The authors’ conclusion is that the AGEs-RAGE axis and the mitochondrial-derived peptides are biologically linked but follow partially overlapping and distinct pathways, which is a careful way of saying the class should not be treated as one variable.
The negative worth keeping
Protein-energy wasting showed no association with any of the AGEs-RAGE components or with the mitochondrial-derived peptides. C-reactive protein was associated with the AGEs to sRAGE ratio.
Protein-energy wasting is a defined syndrome in advanced kidney disease covering loss of muscle and fat with low protein reserves, and it is a strong predictor of outcome. If MOTS-c were simply a proxy for how depleted a patient is, it should have moved with it. It did not.
Inflammation did move with the ratio, which suggests the axis being measured here has more to do with inflammatory and glycation load than with nutritional depletion. That is a genuinely informative null result, and it narrows what a MOTS-c measurement in this population can be interpreted as.
What this design cannot tell you
Everything above is correlation in a single blood draw.
The study is cross-sectional, so there is no direction. A lower peptide concentration could reflect mitochondrial dysfunction caused by the disease, a response to it, or an unrelated consequence of reduced muscle mass in a population where muscle is the presumed source.
The population is also selected. These were patients accepted for living-donor transplantation, which means they were well enough to be listed and to have a donor. They are not representative of kidney failure in general, and any comparison against 80 controls carries that constraint.
And the peptides were measured by ELISA, which quantifies immunoreactivity rather than confirming sequence. For short peptides in serum that distinction matters, because antibody cross-reactivity is a known difficulty in this literature.
How it fits with the rest of the MOTS-c record
The same institution reported in 2019 that skeletal muscle expression of humanin, MOTS-c and Nrf2 was reduced in chronic kidney disease. That was tissue expression. This is circulating concentration, in a larger cohort, with the glycation axis measured alongside.
Pointing the other way, a 2021 study reported that acute endurance exercise raises circulating mitochondrial-derived peptides in humans, which is the counterpart finding: the same measurement goes up with an acute mitochondrial demand and down in chronic disease.
We have covered this compound from three other directions. A sepsis cardiomyopathy model tested it as an intervention in animals. The microprotein family it belongs to was the subject of a broader piece on short open reading frames. A systematic review of exercise studies covered the physiology in healthy people.
This paper is the first human disease cohort of the four, and it is measuring the peptide as a marker rather than testing it as an agent. Those are different questions and the literature routinely blurs them.
What it means for the catalogue
A laboratory buying reference material for assay work has a specific use for a paper like this, and it is not the biology.
The study establishes what concentrations look like in a large diseased cohort and in controls, which is the kind of range information an assay developer needs and which is usually missing. It also flags the humanin and MOTS-c divergence, which is a reason to measure both rather than either.
Retatrutide appears in our coverage of kidney work through a comparison of renal fibrosis models, and it is worth noting how different the two literatures are. One compound is being examined as a marker of a disease process, the other as an agent acting on it. Neither result transfers to the other.
For laboratories, our European research buyer guide covers procurement and documentation, everything is supplied on a research use only basis, and our ranking of the most-studied research peptides tracks the published record for each compound.
References
- Suliman ME, Rahman A, Qureshi AR, Barany P, Stenvinkel P, Kublickiene K, Lindholm B. AGEs-RAGE Axis and Mitochondrial-Derived Peptides in Advanced Chronic Kidney Disease: Interconnected Pathways Beyond Inflammation and Nutrition. Antioxidants (Basel), 30 July 2026, 15(8):956. doi 10.3390/antiox15080956
- Liu C, Gidlund EK, Witasp A, Qureshi AR, Söderberg M, Thorell A, et al. Reduced skeletal muscle expression of mitochondrial-derived peptides humanin and MOTS-C and Nrf2 in chronic kidney disease. American Journal of Physiology Renal Physiology, 1 November 2019, 317(5):F1122-F1131
- von Walden F, Fernandez-Gonzalo R, Norrbom J, Emanuelsson EB, Figueiredo VC, Gidlund EK, et al. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans. Journal of Applied Physiology, 1 September 2021, 131(3):1035-1042
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