Humanin and MOTS-c Attenuate Atrial Fibrillation by Suppressing Fibrosis and Mitochondrial Dysfunction.
This study investigated the role of two mitochondrial-derived peptides (MDPs) — humanin (HN) and MOTS-c — in atrial fibrillation (AF), a common heart rhythm disorder. Researchers first examined human atrial tissue using public gene expression data, immunohistochemistry, and immunofluorescence, and measured plasma levels in a matched cohort of 39 AF patients and 39 sinus rhythm controls. They found that both peptides were significantly downregulated in AF tissue, with levels inversely correlated with fibrosis extent. Plasma MOTS-c was also reduced in AF patients and inversely correlated with NT-proBNP, a heart stress biomarker. Using an angiotensin II (AngII)-induced mouse AF model (n=36, male C57BL/6J), the study found that treatment with HNG (an HN analogue) or MOTS-c reduced AF inducibility and attenuated atrial fibrosis and hypertrophy. Peptide treatment was associated with improved mitochondrial structure, reduced fission proteins (Drp1, Fis1), and lower inflammatory cytokines. In vitro experiments in rat cardiomyocytes and fibroblasts showed reduced oxidative stress, fibroblast activation, proliferation, and migration. Exploratory RNA-sequencing suggested distinct mechanistic pathways. Key limitations include the small human cohort, the use of an animal model that may not fully replicate clinical AF, and the exploratory nature of mechanistic findings.
Why this grade: Human data are limited to a small matched observational cohort (n=39 per group) with no interventional component; therapeutic findings derive from a mouse model and in vitro cell experiments, not human trials.
Background: Atrial fibrillation (AF) is a common clinical arrhythmia associated with mitochondrial dysfunction, oxidative stress, and atrial fibrosis. Mitochondrial-derived peptides (MDPs), including humanin (HN) and MOTS-c, exhibit cytoprotective properties, but their role in AF remains largely unknown. Objective: This study aimed to investigate the expression of HN and MOTS-c in AF patients and to evaluate their therapeutic potential and underlying mechanisms in an AngII-induced mouse model and primary cardiac cells. Methods: HN and MOTS-c expression in human atrial tissues was analyzed using public GEO data, immunohistochemistry, and immunofluorescence. Plasma levels were measured in a matched cohort (39 AF patients, 39 sinus rhythm controls). Murine AF models (male C57BL/6J mice, n = 36) and primary rat cardiomyocytes and fibroblasts were exposed to angiotensin II (AngII) with or without treatment with HNG (an HN analogue) or MOTS-c. Results: 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 and inversely correlated with NT-proBNP. In vivo, HNG or MOTS-c treatment reduced AF inducibility and attenuated AngII-induced atrial fibrosis and hypertrophy. Peptide treatment was associated with improved mitochondrial ultrastructure, reduced mitochondrial fission proteins (Drp1, Fis1), and lower pro-inflammatory cytokines (IL-1β, IL-6) in mouse atria. In primary cardiomyocytes, both peptides mitigated AngII-induced oxidative stress. In fibroblasts, they directly inhibited AngII-induced activation, proliferation, and migration. Exploratory RNA-seq suggested that HNG predominantly affects cell adhesion pathways, while MOTS-c acts on metabolic processes. Conclusions: Downregulation of HN and MOTS-c in human AF is associated with disease severity. In murine models, HNG or MOTS-c administration attenuates atrial fibrosis and mitochondrial dysfunction and reduces AF inducibility. These findings suggest that MDPs may represent a novel therapeutic avenue for AF, although further validation with larger cohorts and mechanistic studies are required.
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