Key result
Fibroblast-specific PGC-1α overexpression or METTL3/YTHDF2 knockdown reduces cardiac fibrosis and restores mitochondrial dynamics in mice.
Why the study?
Upstream regulatory mechanisms of dysregulated mitochondrial fission in cardiac fibrosis, particularly the role of N6-methyladenosine epitranscriptomic regulation, remain poorly understood.
Targeting the METTL3/YTHDF2 epitranscriptomic axis presents a promising strategy for therapeutic intervention in cardiac fibrosis by restoring PGC-1α and normalizing mitochondrial dynamics.
Answers are grounded in this paper and cite their sources.
Should not yet change practice in cardiac fibrosis or AF; leaves open m6A epitranscriptomic control of mitochondrial fission for mechanistic and translational study.[[1]](https://link.springer.com/article/10.
Dysregulated mitochondrial fission drives pathological cell states in cardiac fibrosis, but its upstream regulatory mechanisms remain poorly understood. The role of epitranscriptomic regulation, particularly N6-methyladenosine (m6A) modification, in this process has not been defined. We employed integrated approaches including in vitro models of TGF-β1-stimulated cardiac fibroblasts, in vivo mouse models of isoproterenol-induced cardiac fibrosis, and analysis of human atrial fibrillation tissues. Techniques encompassed molecular profiling, m6A-specific assays (MeRIP-qPCR, RIP-qPCR), functional studies, high-resolution imaging, and fibroblast-targeted AAV9-mediated gene manipulation. METTL3 and YTHDF2 were significantly upregulated in experimental and human fibrotic hearts. METTL3 mediated m6A modification of PGC-1α mRNA, enhancing its recognition and degradation by YTHDF2. This suppression of PGC-1α led to excessive Drp1-dependent mitochondrial fission, which in turn promoted cardiac fibroblast proliferation, migration, and extracellular matrix production. Inhibition of METTL3 or YTHDF2 restored PGC-1α expression, normalized mitochondrial dynamics, and attenuated fibrotic responses in vitro. Fibroblast-specific knockdown of METTL3 or YTHDF2 in vivo robustly ameliorated fibrosis, improved mitochondrial ultrastructure, and restored systolic function. In human atrial fibrillation, activation of this axis correlated with suppressed PGC-1α, enhanced mitochondrial fission, and disease severity. Our findings introduce a novel epitranscriptomic pathway involving METTL3 and YTHDF2, which regulates PGC-1α through m6A modification. Targeting this axis presents a promising strategy for therapeutic intervention in cardiac fibrosis, offering new insights into both the molecular mechanisms driving fibrosis and potential treatment avenues.
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Cao et al. (2026) studied Cardiac fibrosis (n=68). AAV9-mediated gene manipulation (AAV9-POSTN-OE-PGC1α, AAV9-shYTHDF2, AAV9-shMETTL3) vs. AAV9-POSTN-NC (control virus) or no virus control was evaluated on Cardiac fibrosis and mitochondrial fragmentation. Fibroblast-specific overexpression of PGC-1α or knockdown of METTL3 and YTHDF2 ameliorated isoproterenol-induced cardiac fibrosis and restored mitochondrial dynamics in mice.
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