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MOTS-c vs humanin

MOTS-c and humanin are both encoded in mitochondrial rRNA genes. How their discovery, sequence and evidence base compare, with the studies that measured both.

By the MOTS-C Peptide editorial teamLast reviewed November 11, 2026Sources: editorially approved

Short answer

MOTS-c and humanin are both peptides encoded inside mitochondrial ribosomal RNA genes, which is why they are grouped together as mitochondrial-derived peptides. They come from different genes, differ in length, and were found 14 years apart in unrelated lines of research: humanin in 2001 from work on neuronal survival [Hashimoto 2001], MOTS-c in 2015 from work on metabolism [Lee et al. 2015].

MOTS-c and Humanin compared field by field. Each column describes that substance only; the rows are not scores.
	MOTS-c	Humanin
What it is	A 16-amino-acid peptide	A 24-amino-acid peptide
Encoded in	MT-RNR1, the mitochondrial 12S rRNA gene	MT-RNR2, the mitochondrial 16S rRNA gene
Sequence	MRWQEMGYIFYPRKLR	MAPRGFSCLLLLTSEIDLPVKRRA
First described	2015, in work on metabolic homeostasis	2001, in a screen for factors protecting neurons
Research framing	Metabolism, insulin sensitivity, exercise capacity, AMPK signalling	Neuronal survival, cytoprotection, apoptosis, aging
Records in this index	253 indexed publicationsThis index is built from a MOTS-c search, so it undercounts the humanin literature.	61 of them also involve humanin
Human intervention trials published	None	None
Approved use	None	None

Why they are grouped together

The mitochondrial genome was long thought to encode only 13 proteins plus the RNAs needed to translate them. Humanin was the first peptide found hiding inside one of those RNA genes [Hashimoto 2001], MOTS-c the second [Lee et al. 2015], and a family of small humanin-like peptides, SHLP1 to SHLP6, was later described in the same 16S region as humanin [Cobb 2016].

What unites them is where their coding sequence sits, not how they work. They share no receptor, no established common pathway and no sequence similarity. Treating a finding about one as support for the other is a category error, and a common one in writing that discusses them interchangeably.

Where they are studied together

Of the 61 overlapping records, 22 involve human participants. The recurring design is a cohort study that draws blood, measures both peptides by immunoassay, and asks whether levels differ between groups. They appear together in work on kidney disease, cardiovascular disease, exercise responses and cancer risk stratification.

That pairing is a practical choice as much as a biological one: once a laboratory has plasma and runs one mitochondrial-peptide assay, running the second is cheap. It explains why the two names appear together so often without implying that they act together.

Indexed records involving both MOTS-c and humanin, ranked by evidence tier
Study	Model	What was reported	Limitations	Tier
Suliman 2026 Antioxidants (Basel) Related mitochondrial peptide	Human obs. Adults with kidney failure undergoing living-donor kidney transplantation and controls; serum AGEs, RAGE isoforms and MDPs by ELISA	Measured higher advanced glycation end-products and lower mitochondrial-derived peptides, including MOTS-c, in adults with chronic kidney disease compared with controls. Reported that MOTS-c was inversely associated with advanced glycation end-products and with the AGEs/sRAGE ratio, while humanin was independently associated with AGEs and sRAGE measures.	Cross-sectional design with MOTS-c one of several peptides measured; single-centre transplantation cohort; ELISA-based peptide quantification without orthogonal confirmation.	Evidence tier B
Horwath 2026 Exp Physiol Endogenous MOTS-c measured	Human obs. Adults with cerebral palsy using running frames and typically developing adults and adolescents; plasma MDPs before and after endurance exercise	Measured plasma MOTS-c, humanin and SHMOOSE in adults with cerebral palsy and typically developing participants and found comparable basal levels despite lower muscle mass and peak oxygen uptake in the cerebral palsy group. Reported no or only modest changes in circulating MDPs after an acute endurance exercise bout, with no differences between groups.	Small group sizes not reported in the abstract; single post-exercise sampling point; in-house ELISA without external validation and heterogeneous exercise modes between groups.	Evidence tier B
Rodríguez-Esparragón 2025 Int J Mol Sci Several	Human obs. Patients with Alzheimer's disease or mild cognitive impairment and individuals with subjective cognitive decline as controls	Reported that blood and plasma transcript levels of humanin and MOTS-c, normalised to mitochondrial DNA copy number, differed significantly across groups and were lower in adults with Alzheimer's disease than in those with subjective cognitive decline. Found that plasma protein concentrations of the two peptides did not distinguish Alzheimer's disease from mild cognitive impairment. Reported in decay assays faster degradation of humanin mRNA and delayed but stable recovery of MOTS-c mRNA.	Cross-sectional case-control comparison with no group sizes reported in the abstract, controls defined as subjective cognitive decline rather than healthy individuals, and transcript-level findings not corroborated by circulating protein measurements.	Evidence tier B
Jelinek 2025 Sci Rep Endogenous MOTS-c measured	Human obs. Adults stratified by HbA1c into normoglycaemic, prediabetic and diabetic groups with clinical, oxidative, inflammatory and mitochondrial biomarkers	Applied random forest and hierarchical random forest models to predict the atherogenic index of plasma in adults stratified by HbA1c. Reported that mitochondrial redox markers including humanin ranked among the top predictors in the normoglycaemic group, that oxidative stress markers were more informative in prediabetes, and that MOTS-c and IL-1β were key features in the group with diabetes, with waist-to-height ratio the main contributing variable overall.	Cross-sectional design with no reported sample size or external validation cohort, so stage-specific feature rankings may not be stable; MOTS-c appears only as one feature in a machine-learning model rather than as a prespecified outcome.	Evidence tier B
Coradduzza 2025 Clin Exp Med Several	Human obs. Male patients investigated for suspected prostate cancer, grouped as benign hyperplasia, precancerous lesions or prostate cancer	Measured circulating humanin and MOTS-c, GAS5 and exosomal miR-21 and miR-103 in men investigated for prostate disease. Found lower humanin and GAS5 in precancerous lesions and prostate cancer than in benign prostatic hyperplasia, higher exosomal miR-21 and miR-103 in prostate cancer, and higher MOTS-c in precancerous lesions than in benign prostatic hyperplasia. Reported that a plasma model combining humanin, GAS5 and MOTS-c reached 95% cross-validated classification accuracy across these clinical groups.	Single cross-sectional cohort with no external validation, and near-perfect reported AUCs raise the possibility of overfitting; group sizes are not given, men only by disease definition, and MOTS-c is one of several biomarkers rather than the primary focus.	Evidence tier B
Coskun 2024 Mol Biol Rep Endogenous MOTS-c measured	Human obs. Serum endoglin, VPO1, humanin, MOTS-c and miR-200c in untreated preeclamptic pregnancies and control pregnancies	Measured lower serum MOTS-c in women with untreated preeclampsia than in controls, alongside higher endoglin, VPO1 and miR-200c and no significant difference in humanin.	Sample sizes are not reported and blood was sampled at one time point before treatment; correlations cannot establish direction; the MOTS-c result differs from other preeclampsia reports.	Evidence tier B
Asil 2024 Eur J Pharmacol Endogenous MOTS-c measured	Human obs. Serum MOTS-c, humanin, nitrosative stress and ferroptosis markers in diabetic patients with heart failure with reduced ejection fraction, with or without SGLT2 inhibitor use	Measured higher serum MOTS-c in diabetic patients with heart failure taking SGLT2 inhibitors than in controls, with no corresponding difference in humanin. Also reported higher GPX4 and lower ACSL4 in the SGLT2 inhibitor group, while TFRC was higher in patients and unchanged by SGLT2 inhibitor use.	Non-randomised comparison of existing treatment groups, open to confounding by indication; single time point with modest group sizes and no adjustment described in the abstract.	Evidence tier B
Li 2024 Sleep Med Endogenous MOTS-c measured	Human obs. Neuron-derived exosomal MOTS-c, humanin and neurogranin in adults with obstructive sleep apnea with and without mild cognitive impairment	Measured higher neuron-derived exosomal MOTS-c in adults with obstructive sleep apnea and mild cognitive impairment than in adults with OSA alone or controls, and reported that exosomal MOTS-c mediated part of the association between nocturnal oxygenation measures and cognitive scores. In 22 patients reassessed after a year of CPAP, levels were lower than at baseline.	Mainly cross-sectional with a small, uncontrolled CPAP follow-up subgroup; reported mediation proportions above 100% indicate unstable estimates; single-centre sample.	Evidence tier B
Kavak 2024 Curr Radiopharm Endogenous MOTS-c measured	Human obs. Serum MOTS-c and humanin before, during and after radiotherapy in patients with lung or breast cancer and in healthy volunteers	Measured higher circulating MOTS-c in patients with lung cancer than in controls and a further increase after radiotherapy. In patients with breast cancer, humanin was lower while MOTS-c was not significantly changed.	Small single-centre groups with the control group size not reported; lung cancer patients also received chemotherapy, so changes cannot be attributed to radiotherapy alone.	Evidence tier B
Goetzl 2023 Am J Med Endogenous MOTS-c measured	Human obs. Blood total extracellular vesicles from uninfected, acute COVID-19, PASC and post-acute non-PASC participants	Measured mitochondrial and viral proteins in blood total extracellular vesicles by ELISA in adults across COVID-19 stages. Reported significantly decreased extracellular vesicle levels of MOTS-c, VDAC-1 and humanin, and elevated SARM-1, in acutely infected participants who later developed PASC, and decreased MOTS-c and humanin with elevated SARM-1 in established PASC with neuropsychiatric manifestations.	Small group sizes, particularly the post-acute non-PASC group; observational case-control design with no mechanistic testing; MOTS-c measured only as one of several extracellular-vesicle cargo proteins by ELISA.	Evidence tier B

Where the evidence actually differs

Humanin has the longer history, and its early work established the idea that a mitochondrial rRNA gene could yield a biologically active peptide at all. MOTS-c arrived into a field that was already prepared for it, which is part of why its metabolic framing was taken up quickly.

One senescence study gives a sense of how closely their behaviour tracks: in senescent human fibroblasts, both peptides were elevated, and administering either modestly increased mitochondrial respiration [Kim et al. 2018]. A difference worth noting is the nuclear work: MOTS-c has a specific reported behaviour, translocating to the nucleus under metabolic stress [Kim et al. 2018], that is not part of the humanin account.

What is the same for both

Neither is an approved medicine. Neither has a published randomised controlled trial of the administered peptide in people. For both, the human literature consists largely of measuring what the body already makes and comparing groups. FDA’s 2026 review of MOTS-c noted that its molecular target remains unknown [FDA 2026]; the same gap applies to this class generally.

See mitochondrial research for how this family is studied, and human studies for what has been measured in people.

Frequently asked questions

What is the difference between MOTS-c and humanin?

Both are peptides encoded inside mitochondrial ribosomal RNA genes, but in different ones: humanin comes from the 16S rRNA gene MT-RNR2 and is 24 amino acids long, while MOTS-c comes from the 12S rRNA gene MT-RNR1 and is 16 amino acids long. Humanin was described in 2001 from work on neuronal survival; MOTS-c in 2015 from work on metabolism.

Are MOTS-c and humanin the same family?

They are both called mitochondrial-derived peptides, along with the small humanin-like peptides SHLP1 to SHLP6. The grouping describes where they are encoded, not a shared mechanism or a shared receptor.

Which has more research behind it?

Humanin was described 14 years earlier and has the longer literature. Within this MOTS-c index, 61 of the 253 records also involve humanin, most often because a study measured both in the same blood samples.

Is either one approved?

Neither is an approved medicine anywhere, and neither has a published randomised controlled trial of the administered peptide in people.

Do studies measure them together?

Often. Because both are measured by immunoassay in plasma, cohort studies frequently report them side by side as candidate biomarkers. Those studies measure the peptides people already produce; they do not give either one.

References

Lee C, Zeng J, Drew BG et al. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. PubMed 25738459 · doi:10.1016/j.cmet.2015.02.009 · Study record[Animal, tier C]
Kim SJ, Mehta HH, Wan J et al. (2018). Mitochondrial peptides modulate mitochondrial function during cellular senescence. Aging (Albany NY). PubMed 29886458 · doi:10.18632/aging.101463 · Study record[Cells, tier D]
Kim KH, Son JM, Benayoun BA et al. (2018). The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metab. PubMed 29983246 · doi:10.1016/j.cmet.2018.06.008 · Study record[Cells, tier D]
Hashimoto Y et al., Proc Natl Acad Sci U S A (2001-05-22). A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta. Source[retrieved 2026-11-11]
UniProt Consortium (2026-09-02). UniProtKB A0A0C5B5G6 (MOTSC_HUMAN): Mitochondrial-derived peptide MOTS-c. Source[retrieved 2026-11-11]
UniProt Consortium. UniProtKB Q8IVG9 (HUNIN_HUMAN): Humanin. Source[retrieved 2026-11-11]
Cobb LJ et al., Aging (Albany NY) (2016-04). Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Source[retrieved 2026-11-11]
U.S. Food and Drug Administration (2026-05-11). FDA Briefing Document: MOTS-c-Related Bulk Drug Substances (MOTS-c (free base) and MOTS-c acetate). Source[retrieved 2026-11-11]