Humanin and MOTS-c Attenuate Atrial Fibrillation by Suppressing Fibrosis and Mitochondrial Dysfunction
Background
Atrial fibrillation (AF) is a prevalent cardiac arrhythmia characterized by mitochondrial dysfunction, oxidative stress, and atrial fibrosis. Current therapeutic strategies often fall short in addressing these underlying cellular pathologies, leading to persistent disease burden. Mitochondrial-derived peptides (MDPs), including Humanin (HN) and MOTS-c, are emerging as cytoprotective agents with broad metabolic and anti-inflammatory properties. However, their specific roles and therapeutic potential in the context of AF pathophysiology have remained largely unexplored.
Study Design
Researchers investigated HN and MOTS-c expression in human atrial tissues using public GEO data, immunohistochemistry, and immunofluorescence. Plasma levels were measured in a matched cohort of 39 AF patients and 39 sinus rhythm controls. An in vivo murine AF model (male C57BL/6J mice, n = 36) was induced by angiotensin II (AngII) and treated with either HNG (a Humanin analogue) or MOTS-c. Primary rat cardiomyocytes and fibroblasts were also exposed to AngII with or without peptide treatment. Primary endpoints included AF inducibility, atrial fibrosis, hypertrophy, mitochondrial ultrastructure, and inflammatory markers, assessed via ELISA, qPCR, and RNA-seq.
Results
HN and MOTS-c were significantly downregulated in human AF atrial tissue, with levels inversely correlating with fibrosis extent. Plasma MOTS-c was decreased in AF patients and inversely correlated with NT-proBNP. In the AngII-induced mouse model, treatment with HNG or MOTS-c 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.
In vivo, HNG or MOTS-c treatment reduced AF inducibility and attenuated AngII-induced atrial fibrosis and hypertrophy, highlighting their therapeutic potential.
Key Findings
- Humanin and MOTS-c were significantly downregulated in human AF atrial tissue, inversely correlating with fibrosis.
- Plasma MOTS-c was decreased in AF patients and inversely correlated with
NT-proBNP. - HNG or MOTS-c treatment reduced AF inducibility and attenuated AngII-induced atrial fibrosis and hypertrophy in mice.
- Peptide treatment improved mitochondrial ultrastructure and reduced fission proteins (
Drp1,Fis1) and pro-inflammatory cytokines (IL-1β,IL-6). - Both peptides mitigated AngII-induced oxidative stress in cardiomyocytes and inhibited fibroblast activation/proliferation/migration.
Why It Matters
This research suggests that Humanin and MOTS-c offer a novel therapeutic strategy for atrial fibrillation, by directly targeting the underlying mechanisms of fibrosis and mitochondrial dysfunction, which are often poorly addressed by conventional antiarrhythmics. For peptide users and biohackers, this opens a new avenue for exploring mitochondrial-derived peptides in cardiovascular health, particularly for conditions involving mitochondrial stress and fibrotic remodeling. While preclinical, these findings provide a strong rationale for future clinical investigations into HN analogues or MOTS-c as potential preventative or adjunctive therapies for AF, moving beyond symptomatic management towards disease modification. Further research is needed to establish human-specific dosing and protocols.
humanin
mots-c
atrial-fibrillation
fibrosis
mitochondrial-dysfunction
inflammation