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The m6A methyltransferase METTL3 modifies PGC-1α mRNA promoting mitochondrial dysfunction and oxLDL-induced
Xinning Zhang1, Xin Li1, Hongti Jia1
1Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University, Beijing, China.
Abstract:
Mitochondrial biogenesis and energy metabolism are essential for regulating the inflammatory state of monocytes. This state is partially controlled by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a coactivator that regulates mitochondrial biogenesis and energy metabolism. Disruption of these processes can also contribute to the initiation of chronic inflammatory diseases, such as pulmonary fibrosis, atherosclerosis, and rheumatoid arthritis. Methyltransferase-like 3 (METTL3)-dependent N6-methyladenosine (m6A) methylation has recently been shown to regulate a variety of inflammatory processes. However, the role of m6A mRNA methylation in affecting mitochondrial metabolism in monocytes under inflammation is unclear, nor is there an established relationship between m6A methylation and PGC-1α. In this study, we identified a novel mechanism by which METTL3 acts during oxidized low-density lipoprotein (oxLDL)-induced monocyte inflammation, where METTL3 and YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) cooperatively modify PGC-1α mRNA, mediating its degradation, decreasing PGC-1α protein levels, and thereby enhancing the inflammatory response. METTL3 coordinated with YTHDF2 to suppress the expression of PGC-1α, as well as that of cytochrome c (CYCS) and NADH:ubiquinone oxidoreductase subunit C2 (NDUFC2) and reduced ATP production and oxygen consumption rate (OCR). This subsequently increased the accumulation of cellular and mitochondrial reactive oxygen species (ROS) and the levels of proinflammatory cytokines in inflammatory monocytes. These data may provide new insights into the role of METTL3-dependent m6A modification of PGC-1α mRNA in the monocyte inflammation response. These data also contribute to a more comprehensive understanding of the pathogenesis of monocyte-macrophage inflammation-associated diseases, such as pulmonary fibrosis, atherosclerosis, and rheumatoid arthritis.
Insights
Methyltransferase-like 3 (METTL3) and YTHDF2 target PGC-1α mRNA, reducing mitochondrial function and increasing inflammation in monocytes. This reveals a new pathway in inflammatory diseases.
Area of Science:
- Molecular Biology
- Immunology
- Metabolism
Background:
- Mitochondrial function regulates monocyte inflammation, influenced by PGC-1α.
- METTL3-dependent m6A methylation impacts inflammation, but its role in monocyte mitochondrial metabolism is unknown.
- Chronic inflammatory diseases involve disrupted mitochondrial processes.
Purpose of the Study:
- Investigate the role of METTL3-dependent m6A methylation in PGC-1α regulation during monocyte inflammation.
- Elucidate the mechanism linking METTL3, m6A, and mitochondrial metabolism in monocytes.
- Explore the connection between m6A and PGC-1α in inflammatory responses.
Main Methods:
- Studied METTL3 and YTHDF2 interaction with PGC-1α mRNA in oxidized LDL-induced monocyte inflammation.
- Assessed PGC-1α protein levels, mRNA degradation, ATP production, and oxygen consumption rate (OCR).
- Measured reactive oxygen species (ROS) and proinflammatory cytokine levels.
Main Results:
- METTL3 and YTHDF2 cooperatively degrade PGC-1α mRNA, reducing PGC-1α protein.
- Suppressed PGC-1α led to decreased CYCS and NDUFC2 expression, reduced ATP production, and lower OCR.
- Increased ROS accumulation and proinflammatory cytokines were observed in inflammatory monocytes.
Conclusions:
- METTL3-dependent m6A modification of PGC-1α mRNA is a novel mechanism in monocyte inflammation.
- This pathway impairs mitochondrial metabolism and enhances inflammatory responses.
- Findings offer insights into monocyte-macrophage inflammation-associated diseases like atherosclerosis and rheumatoid arthritis.
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