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FTO Alleviates COPD Pathogenesis by Demethylating S100A9 to Suppress ERK1/2-Drp1-Driven Mitophagy
Bin Xie1,2,3, Qiong Chen1,3, Ziyu Dai1,2,3
1Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
Rationale:
N6-methyladenosine (m6A) modifications are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), yet the precise role of the demethylase fat mass and obesity-associated protein (FTO) remains unclear.
Objectives:
To identify whether FTO acts as a suppressor of COPD pathogenesis and to elucidate the underlying epitranscriptomic mechanism.
Methods:
COPD models were established using cigarette smoke-exposed mice and cigarette smoke extract-stimulated BEAS-2B cells. FTO expression was modulated by lentiviral transduction. m6A epitranscriptomic microarray, RNA immunoprecipitation, m6A methylation analysis, and mRNA stability assays were performed. Inflammation, oxidative stress, mitophagy, and ERK1/2-Drp1 signaling were assessed.
Results:
FTO expression is reduced in COPD patients and murine models, correlating with elevated m6A levels and disease severity. Overexpression of FTO mitigates inflammation, oxidative stress, and mitochondrial dysfunction by destabilizing S100 calcium-binding protein A9 (S100A9) mRNA via m6A demethylation. Mechanistically, FTO inhibits the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2)- dynamin-related protein 1 (Drp1), thereby suppressing excessive mitophagy and preserving mitochondrial integrity. Notably, S100A9 overexpression abolishes the protective effects of FTO, establishing the FTO/S100A9 axis as a central regulator.
Conclusions:
FTO attenuates COPD pathogenesis by demethylating S100A9 mRNA, thereby suppressing ERK1/2-Drp1-driven mitophagy. The FTO/S100A9 axis represents a novel epitranscriptomic mechanism and a potential therapeutic target for COPD.
Insights
The fat mass and obesity-associated protein (FTO) demethylase suppresses chronic obstructive pulmonary disease (COPD) by reducing S100A9 mRNA levels. This mechanism involves inhibiting ERK1/2-Drp1 signaling and mitophagy, offering a new therapeutic target for COPD.
Area of Science:
- Epitranscriptomics
- Molecular Biology
- Pulmonary Medicine
Background:
- N6-methyladenosine (m6A) modifications are linked to chronic obstructive pulmonary disease (COPD) pathogenesis.
- The specific role of the m6A demethylase, fat mass and obesity-associated protein (FTO), in COPD is not well understood.
Purpose of the Study:
- To investigate FTO's suppressive role in COPD pathogenesis.
- To elucidate the underlying epitranscriptomic mechanisms involving FTO in COPD.
Main Methods:
- Established COPD models using cigarette smoke-exposed mice and BEAS-2B cells.
- Modulated FTO expression and performed m6A epitranscriptomic microarray, RNA immunoprecipitation, and mRNA stability assays.
- Assessed inflammation, oxidative stress, mitophagy, and ERK1/2-Drp1 signaling pathways.
Main Results:
- Reduced FTO expression and elevated m6A levels correlated with COPD severity in patients and models.
- FTO overexpression mitigated COPD hallmarks by destabilizing S100 calcium-binding protein A9 (S100A9) mRNA via m6A demethylation.
- FTO inhibited ERK1/2-Drp1 phosphorylation, suppressing mitophagy and preserving mitochondrial integrity; S100A9 overexpression reversed FTO's protective effects.
Conclusions:
- FTO attenuates COPD pathogenesis by targeting S100A9 mRNA, thereby inhibiting ERK1/2-Drp1-driven mitophagy.
- The FTO/S100A9 axis presents a novel epitranscriptomic mechanism in COPD.
- This axis is a potential therapeutic target for COPD treatment.
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