Humanin and MOTS-c Attenuate Atrial Fibrillation by Suppressing Fibrosis and Mitochondrial Dysfunction. — VialBase Research
First evidence that MOTS-c is depleted in human atrial fibrillation and that restoring it reduces atrial fibrosis, mitochondrial dysfunction, and AF inducibility in mice.
- Humanin (HN) and MOTS-c were significantly downregulated in human AF atrial tissue, with levels inversely correlated with the extent of fibrosis
- Plasma MOTS-c was decreased in AF patients (matched cohort: 39 AF patients vs 39 sinus rhythm controls) and inversely correlated with NT-proBNP
- In male C57BL/6J mice (n = 36), HNG (an HN analogue) or MOTS-c treatment reduced AF inducibility and attenuated AngII-induced atrial fibrosis and hypertrophy
- Peptide treatment improved mitochondrial ultrastructure, reduced mitochondrial fission proteins (Drp1, Fis1), and lowered pro-inflammatory cytokines (IL-1β, IL-6) in mouse atria
- In primary cardiomyocytes both peptides mitigated AngII-induced oxidative stress; in fibroblasts they inhibited AngII-induced activation, proliferation, and migration, with RNA-seq suggesting MOTS-c acts on metabolic processes and HNG on cell adhesion pathways
Summary
This translational study examined the mitochondrial-derived peptides humanin (HN) and MOTS-c in atrial fibrillation (AF). The authors profiled HN and MOTS-c in human atrial tissue (public GEO data, immunohistochemistry, immunofluorescence) and plasma (39 AF patients vs 39 sinus rhythm controls), then tested the HN analogue HNG and MOTS-c in an angiotensin II (AngII)-induced mouse AF model (male C57BL/6J, n = 36) and in primary rat cardiomyocytes and fibroblasts. Both peptides were depleted in AF and, when administered, attenuated fibrosis, mitochondrial dysfunction, and AF inducibility.
Key Findings
- HN and MOTS-c were significantly downregulated in human AF atrial tissue, and their levels inversely correlated with fibrosis extent
- Plasma MOTS-c was decreased in AF patients (39 AF vs 39 sinus rhythm controls) and inversely correlated with NT-proBNP
- In vivo, HNG or MOTS-c treatment reduced AF inducibility and attenuated AngII-induced atrial fibrosis and hypertrophy
- Treatment improved mitochondrial ultrastructure, reduced mitochondrial fission proteins (Drp1, Fis1), and lowered pro-inflammatory cytokines (IL-1β, IL-6) in mouse atria
- In primary cardiomyocytes, both peptides mitigated AngII-induced oxidative stress; in fibroblasts they inhibited AngII-induced activation, proliferation, and migration
- Exploratory RNA-seq suggested HNG predominantly affects cell adhesion pathways while MOTS-c acts on metabolic processes
Relevance to MOTS-c
This is the first study to link MOTS-c depletion to atrial fibrillation in humans and to show that restoring it is cardioprotective in a preclinical model. It extends MOTS-c biology into cardiac electrophysiology and fibrosis, complementing work on the related mitochondrial-derived peptide Humanin, which was tested here in parallel as the analogue HNG. The inverse correlation between plasma MOTS-c and NT-proBNP suggests a possible biomarker role, though the authors stress that larger cohorts and mechanistic studies are needed before clinical translation.
Citation
Liao Y, Xu J, Jiao Y, et al. Humanin and MOTS-c Attenuate Atrial Fibrillation by Suppressing Fibrosis and Mitochondrial Dysfunction. Biomedicines. 2026. doi:10.3390/biomedicines14051048.
See Also
- Parent compound: MOTS-c
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