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Updated: Jun 12, 2025
Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice
Published on: February 9, 2014
N6-methyladenosine demethyltransferase FTO alleviates sepsis by upregulating BNIP3 to induce mitophagy
Pingping Qi1, Wei Zhang2, Yang Gao3
1The Second Affiliated Hospital of Guangxi Medical University Blood Transfusion Department, Nanning, 533000, Guangxi, People's Repulic of China.
Abstract:
N6-methyladenosine (m6A) is known to be crucial in various biological processes, but its role in sepsis-induced circulatory and cardiac dysfunction is not well understood. Specifically, mitophagy, a specialized form of autophagy, is excessively activated during lipopolysaccharide (LPS)-induced myocardial injury. This study aimed to investigate the impact of LPS-induced endotoxemia on m6A-RNA methylation and its role in regulating mitophagy in sepsis-induced myocardial dysfunction. Our research demonstrated that FTO (fat mass and obesity-associated protein), an m6A demethylase, significantly affects abnormal m6A modification in the myocardium and cardiomyocytes following LPS treatment. In mice, cardiac dysfunction and cardiomyocyte apoptosis worsened after adeno-associated virus serotype 9 (AAV9)-mediated FTO knockdown. Further analyses to uncover the cellular mechanisms improving cardiac function showed that FTO reduced mitochondrial reactive oxygen species, restored both basal and maximal respiration, and preserved mitochondrial membrane potential. We revealed that FTO plays a critical role in activating mitophagy by targeting BNIP3. Additionally, the cardioprotective effects of AAV-FTO were significantly compromised by mdivi-1, a mitophagy inhibitor. Mechanistically, FTO interacted with BNIP3 transcripts and regulated their expression in an m6A-dependent manner. Following FTO silencing, BNIP3 transcripts with elevated m6A modification levels in their coding regions were bound by YTHDF2 (YT521-B homology m6A RNA-binding protein 2), leading to mRNA destabilization and decreased BNIP3 protein levels. These findings highlight the importance of FTO-dependent cardiac m6A methylation in regulating mitophagy and enhance our understanding of this critical interplay, which is essential for developing therapeutic strategies to protect cardiac mitochondrial function, alleviate cardiac dysfunction, and improve survival during sepsis.
Insights
Fat mass and obesity-associated protein (FTO) regulates mitophagy in sepsis-induced heart dysfunction. FTO protects cardiac function by promoting mitophagy and stabilizing BNIP3, offering therapeutic potential.
Area of Science:
- Molecular Biology
- Cardiovascular Biology
- Epigenetics
Background:
- N6-methyladenosine (m6A) is vital in biological processes, but its role in sepsis-induced cardiac dysfunction remains unclear.
- Mitophagy, a key process in myocardial injury during sepsis, is excessively activated.
- Lipopolysaccharide (LPS) induces myocardial injury and cardiac dysfunction.
Purpose of the Study:
- To investigate the impact of LPS-induced endotoxemia on m6A-RNA methylation.
- To elucidate the role of m6A modification in regulating mitophagy in sepsis-induced myocardial dysfunction.
- To explore the function of FTO (fat mass and obesity-associated protein) in cardiac dysfunction.
Main Methods:
- Adeno-associated virus serotype 9 (AAV9)-mediated FTO knockdown in mice.
- Assessment of cardiac function, cardiomyocyte apoptosis, and mitochondrial parameters.
- Analysis of mitophagy activation, FTO-BNIP3 interaction, and m6A modification levels.
- Inhibition of mitophagy using mdivi-1.
Main Results:
- FTO knockdown exacerbated cardiac dysfunction and cardiomyocyte apoptosis in LPS-treated mice.
- FTO reduced mitochondrial oxidative stress, improved respiration, and preserved mitochondrial membrane potential.
- FTO activated mitophagy by targeting BNIP3, with FTO knockdown leading to decreased BNIP3 levels via YTHDF2-mediated mRNA destabilization.
- Cardioprotective effects of FTO were diminished by mitophagy inhibition.
Conclusions:
- FTO plays a critical role in sepsis-induced cardiac dysfunction by regulating m6A-dependent mitophagy.
- FTO targets BNIP3 to promote mitophagy, enhance mitochondrial function, and protect the heart.
- Targeting FTO-mediated m6A modification presents a potential therapeutic strategy for sepsis-induced cardiac dysfunction.
