The m6A methyltransferase METTL3 modifies PGC-1α mRNA promoting mitochondrial dysfunction and oxLDL-induced inflammation in monocytes

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. 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. Monocytes play an important role in the innate immune system and exhibit phagocytic activity to resist viral, bacterial, and fungal infections (1Shi C. Pamer E.G. Monocyte recruitment during infection and inflammation.Nat. Rev. Immunol. 2011; 11: 762-774Crossref PubMed Scopus (1603) Google Scholar, 2Auffray C. Sieweke M.H. Geissmann F. Blood monocytes: Development, heterogeneity, and relationship with dendritic cells.Annu. Rev. Immunol. 2009; 27: 669-692Crossref PubMed Scopus (1104) Google Scholar). Circulating monocytes leave the bloodstream and migrate to inflamed tissues, where they can differentiate into macrophages or dendritic cells following stimulation by interaction with cytokines and/or microbial molecules (e.g., complement proteins, bacterial flagellin, lipopolysaccharide) (2Auffray C. Sieweke M.H. Geissmann F. Blood monocytes: Development, heterogeneity, and relationship with dendritic cells.Annu. Rev. Immunol. 2009; 27: 669-692Crossref PubMed Scopus (1104) Google Scholar). Recruitment of monocytes is essential for effective control and clearance of pathogen infections, but persistent monocyte infiltration also contributes to the pathogenesis of chronic inflammatory and degenerative diseases, such as glomerulonephritis, pulmonary fibrosis, atherosclerosis, rheumatoid arthritis, and Alzheimer's disease (3Duffield J.S. Macrophages and immunologic inflammation of the kidney.Semin. Nephrol. 2010; 30: 234-254Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 4Misharin A.V. Morales-Nebreda L. Reyfman P.A. Cuda C.M. Walter J.M. McQuattie-Pimentel A.C. Chen C.-I. Anekalla K.R. Joshi N. Williams K.J.N. Abdala-Valencia H. Yacoub T.J. Chi M. Chiu S. Gonzalez-Gonzalez F.J. et al.Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span.J. Exp. Med. 2017; 214: 2387-2404Crossref PubMed Scopus (382) Google Scholar, 5Woollard K.J. Geissmann F. Monocytes in atherosclerosis: Subsets and functions.Nat. Rev. Cardiol. 2010; 7: 77-86Crossref PubMed Scopus (595) Google Scholar, 6Katschke K.J. Rottman J.B. Ruth J.H. Qin S. Wu L. LaRosa G. Ponath P. Park C.C. Pope R.M. Koch A.E. Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis.Arthritis Rheum. 2001; 44: 1022-1032Crossref PubMed Scopus (248) Google Scholar, 7Zuroff L. Daley D. Black K.L. Koronyo-Hamaoui M. Clearance of cerebral Aβ in Alzheimer's disease: Reassessing the role of microglia and monocytes.Cell Mol. Life Sci. 2017; 74: 2167-2201Crossref PubMed Scopus (117) Google Scholar). OxLDL is immunogenic and activates endothelial cells, monocytes/macrophages and T cells (8Frostegård J. Nilsson J. Haegerstrand A. Hamsten A. Wigzell H. Gidlund M. Oxidized low density lipoprotein induces differentiation and adhesion of human monocytes and the monocytic cell line U937.Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 904-908Crossref PubMed Scopus (285) Google Scholar, 9Frostegård J. Wu R. Giscombe R. Holm G. Lefvert A.K. Nilsson J. Induction of T-cell activation by oxidized low density lipoprotein.Arterioscler. Thromb. 1992; 12: 461-467Crossref PubMed Google Scholar, 10Berliner J.A. Territo M.C. Sevanian A. Ramin S. Kim J.A. Bamshad B. Esterson M. Fogelman A.M. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions.J. Clin. Invest. 1990; 85: 1260-1266Crossref PubMed Scopus (758) Google Scholar), but is toxic and can cause cell death at higher concentrations (8Frostegård J. Nilsson J. Haegerstrand A. Hamsten A. Wigzell H. Gidlund M. Oxidized low density lipoprotein induces differentiation and adhesion of human monocytes and the monocytic cell line U937.Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 904-908Crossref PubMed Scopus (285) Google Scholar, 9Frostegård J. Wu R. Giscombe R. Holm G. Lefvert A.K. Nilsson J. Induction of T-cell activation by oxidized low density lipoprotein.Arterioscler. Thromb. 1992; 12: 461-467Crossref PubMed Google Scholar, 10Berliner J.A. Territo M.C. Sevanian A. Ramin S. Kim J.A. Bamshad B. Esterson M. Fogelman A.M. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions.J. Clin. Invest. 1990; 85: 1260-1266Crossref PubMed Scopus (758) Google Scholar). Mitochondrial function and bioenergetics have gained recent attention for their contributions to chronic inflammatory diseases, as these processes—beyond their conventional role in generating energy—have been demonstrated to play critical roles in immunity (11Chen Y. Yang M. Huang W. Chen W. Zhao Y. Schulte M.L. Volberding P. Gerbec Z. Zimmermann M.T. Zeighami A. Demos W. Zhang J. Knaack D.A. Smith B.C. Cui W. et al.Mitochondrial metabolic reprogramming by CD36 signaling drives macrophage inflammatory responses.Circ. Res. 2019; 125: 1087-1102Crossref PubMed Scopus (36) Google Scholar, 12Zuo H. Wan Y. Metabolic reprogramming in mitochondria of myeloid cells.Cells. 2019; 9: 5Crossref Scopus (18) Google Scholar). For example, mitochondrial constituents (e.g., mtDNA, mtROS, ATP, cardiolipin, N-formyl peptides) can activate innate immune receptors (e.g., FPR1, NLRP3, NLRC4 and TLR9) to promote inflammatory responses. In addition, a change in mitochondrial metabolism can induce monocyte differentiation into different types of macrophages: M1 (proinflammatory) and M2 (anti-inflammatory) macrophages. M1 macrophages rely on glycolysis for energy production and, as such, have a lower ratio of oxidative phosphorylation to glycolysis. In contrast, M2 macrophages preferentially utilize oxidative phosphorylation and have a higher ratio of oxidative phosphorylation to glycolysis. PGC-1α (also known as PPARGC1A), a member of the peroxisome proliferator-activated receptor γ (PPARγ) coactivator family (13Villena J.A. New insights into PGC-1 coactivators: Redefining their role in the regulation of mitochondrial function and beyond.FEBS J. 2015; 282: 647-672Crossref PubMed Scopus (233) Google Scholar), transcriptionally regulates ~70% of respiratory chain complexes, as well as ATP synthases, tricarboxylic acid cycle intermediary enzymes, and fatty acid oxidation (14Dorn G.W. Kitsis R.N. The mitochondrial dynamism-mitophagy-cell death interactome: Multiple roles performed by members of a mitochondrial molecular ensemble.Circ. Res. 2015; 116: 167-182Crossref PubMed Scopus (106) Google Scholar). Dysregulation of PGC-1α may induce aging, metabolic and degenerative diseases, as well as cancer in humans by suppressing mitochondrial biogenesis (15Finck B.N. Kelly D.P. PGC-1 coactivators: Inducible regulators of energy metabolism in health and disease.J. Clin. Invest. 2006; 116: 615-622Crossref PubMed Scopus (1013) Google Scholar, 16Lin J. Handschin C. Spiegelman B.M. Metabolic control through the PGC-1 family of transcription coactivators.Cell Metab. 2005; 1: 361-370Abstract Full Text Full Text PDF PubMed Scopus (1555) Google Scholar). Interestingly, some studies have shown that PGC-1α may regulate inflammatory responses, such as its role in reprogramming energy metabolism of monocyte-macrophages during sepsis, beginning in the early stages of acute inflammation to stages and a to fatty acid oxidation during the acute inflammatory Full Text Full Text PDF PubMed Scopus Google Scholar). m6A is of the in mRNA and a variety of D. S. S. M. L. S. J. N. M. R. G. of the human and m6A RNA by PubMed Scopus Google Scholar). The of m6A methylation is through the activity of and and and M. M. C. RNA expression during PubMed Scopus Google Scholar, Y. The of RNA methylation in and 2019; 9: PubMed Scopus Google Scholar). The m6A modification by family (e.g., and family proteins, as well as (e.g., Y. The of RNA methylation in and 2019; 9: PubMed Scopus Google Scholar, C. regulation by mRNA Rev. Mol. 2017; PubMed Scopus Google Scholar). METTL3 is the subunit of the m6A which a role in m6A These binding to m6A or through to RNA function or mRNA mRNA mRNA mRNA and mRNA Y. The of RNA methylation in and 2019; 9: PubMed Scopus Google Scholar, C. regulation by mRNA Rev. Mol. 2017; PubMed Scopus Google Scholar). studies have demonstrated that m6A a of and and C. regulation by mRNA Rev. Mol. 2017; PubMed Scopus Google Scholar, Yang Y. Chen Chen Zhang C. Zhang Yang et regulates differentiation and Res. 2017; 27: PubMed Scopus (157) Google Scholar, J. Zhang Huang C. H. B. Zhang Yang Yang Y. regulates and by 2019; PubMed Scopus Google Scholar, L. J. G. Wu J. Zhang Huang N. Z. S. M. M. F. mRNA methylation regulates to promote the of 2019; PubMed Scopus Google Scholar, C. J. Y. in m6A methylation and Immunol. 2019; PubMed Scopus Google Scholar). m6A has been shown to play important roles in innate For example, METTL3 fatty acid by the inflammation in cells Zhao J. H. Z. F. H. Y. fatty acid through suppressing inflammation Immunol. 2019; PubMed Scopus Google Scholar). has of in the regulation of inflammatory in human mRNA the a on signaling and inflammatory production Z. R. B. METTL3 regulates of the inflammatory in human Mol. Med. PubMed Scopus Google Scholar). mRNA m6A methylation dendritic cell activation during stimulation H. Huang M. J. Y. L. mRNA methylation dendritic cell 2019; PubMed Scopus Google Scholar). These and have that the expression and role of METTL3 are and cell tissue and the role of METTL3 in inflammatory in a variety of cells has been the role of mRNA m6A modification in mitochondrial function and metabolism during monocyte inflammation is unclear, the between METTL3 and PGC-1α is In the study, the between METTL3 and mitochondrial metabolism in the of monocyte inflammation METTL3 with PGC-1α mRNA, thereby suppressing and protein of METTL3 or YTHDF2 increased PGC-1α mRNA and which reduced mitochondrial and monocyte These that the and interaction between METTL3 and PGC-1α is in monocyte inflammatory response. These data may contribute to a comprehensive understanding of the pathogenesis of monocyte-macrophage inflammation-associated the role of METTL3 in monocyte inflammation, cells with and METTL3 by higher levels of METTL3 for and that inflammation, we mRNA levels of proinflammatory and increased and a to for and METTL3 levels increased to inflammatory a role in of the data expression to between control and METTL3 monocytes. this with and Interestingly, the expression of PGC-1α and The to that and by by the that with the oxidative phosphorylation signaling the the to in and the cells, we identified for interaction with METTL3 that may by METTL3 the role of the METTL3 expression in monocytes by METTL3 METTL3 the mRNA and protein levels of PGC-1α, and and These data that METTL3 may suppress the expression of PGC-1α and mitochondrial respiratory chain and thereby regulating energy metabolism. METTL3-dependent m6A modification can mRNA and Y. The of RNA methylation in and 2019; 9: PubMed Scopus Google Scholar, C. regulation by mRNA Rev. Mol. 2017; PubMed Scopus Google Scholar). METTL3 increased mRNA and protein levels of PGC-1α, and we the role of METTL3 in regulating PGC-1α, and expression at the and to PGC-1α, and in an RNA that PGC-1α mRNA, but and mRNA, with METTL3 on PGC-1α mRNA identified a N6-methyladenosine (m6A) modification Y. P. Zhang Z. Cui of N6-methyladenosine (m6A) on Res. 44: PubMed Scopus Google Scholar). The in the and of PGC-1α mRNA These into of the and of the RNA performed in of these that METTL3 with the and of PGC-1α mRNA the of METTL3 with the PGC-1α mRNA of PGC-1α to an cells with the and a activity increased METTL3 in PGC-1α and but with that with METTL3 This that METTL3 expression with PGC-1α expression and through interaction in the of PGC-1α The role of m6A modification in the regulation of PGC-1α mRNA an RNA in to in m6A modification in PGC-1α In an METTL3 there a in m6A methylation for PGC-1α mRNA with the control that METTL3 reduced levels of PGC-1α mRNA m6A m6A methylation regulates mRNA C. regulation by mRNA Rev. Mol. 2017; PubMed Scopus Google Scholar, Z. A. Y. D. Y. M. G. B. C. regulation of RNA PubMed Scopus Google Scholar), the PGC-1α mRNA expression in cells may have been to increased of the mRNA METTL3 in cells the of PGC-1α mRNA to that expression of METTL3 may the of PGC-1α mRNA which is with PGC-1α mRNA and protein levels in PGC-1α mRNA to interaction with the mechanism by which and METTL3 is PGC-1α to PGC-1α expression in cells which and protein levels, that the expression of and on the of PGC-1α and is by the of YTHDF2 is an protein that and mRNA Z. A. Y. D. Y. M. G. B. C. regulation of RNA PubMed Scopus Google Scholar). YTHDF2 of PGC-1α mRNA by an RNA that YTHDF2 can to PGC-1α mRNA to METTL3 YTHDF2 increased PGC-1α mRNA and protein levels and RNA demonstrated that YTHDF2 increased the of PGC-1α mRNA to and These that YTHDF2 may the PGC-1α mRNA m6A modification and induce degradation, a mechanism by which YTHDF2 and METTL3 may regulate PGC-1α mRNA and PGC-1α has a role in mitochondrial biogenesis and energy METTL3 and YTHDF2 regulate ATP and production of monocytes by and PGC-1α cell by to METTL3 YTHDF2 and and for ATP levels under with a control or METTL3 increased cellular ATP levels by under PGC-1α and METTL3 this in ATP levels in ATP levels in the YTHDF2 and YTHDF2 and PGC-1α increased levels of reactive oxygen species (ROS) are a of mitochondrial to cellular and mitochondrial Interestingly, with cells, cellular levels in cells increased by more this in METTL3 or YTHDF2 with cells with PGC-1α at partially the reduced cellular levels in the METTL3 or YTHDF2 and in mitochondrial levels in METTL3 YTHDF2 and and the role of METTL3 and YTHDF2 in mitochondrial we oxygen consumption rate in cell of METTL3 YTHDF2 and which by shown in of METTL3 or YTHDF2 increased and of or this also to mitochondria function in control cells, METTL3 cells, and YTHDF2 shown in METTL3 or YTHDF2 increased mitochondrial the of PGC-1α mitochondrial These that METTL3 and YTHDF2 mitochondrial function by PGC-1α METTL3 expression increased during monocyte inflammation the role of METTL3 in monocyte inflammation, the mRNA and protein expression levels of proinflammatory cytokines and in cell of METTL3 and that and mRNA levels increased by in control cells of the METTL3 mRNA levels which partially in the PGC-1α These that METTL3 PGC-1α the inflammatory by In to proinflammatory inflammatory monocytes adhesion molecules under inflammation (2Auffray C. Sieweke M.H. Geissmann F. Blood monocytes: Development, heterogeneity, and relationship with dendritic cells.Annu. Rev. Immunol. 2009; 27: 669-692Crossref PubMed Scopus (1104) Google Scholar, 5Woollard K.J. Geissmann F. Monocytes in atherosclerosis: Subsets and functions.Nat. Rev. Cardiol. 2010; 7: 77-86Crossref PubMed Scopus (595) Google we the expression of adhesion molecules and by and increased METTL3 reduced the and protein This partially in the PGC-1α In addition, adhesion interaction between METTL3 cells and cells, and this in the PGC-1α these that METTL3 mitochondrial and inflammation of monocytes. In to mediating monocytes also contribute to inflammatory (3Duffield J.S. Macrophages and immunologic inflammation of the kidney.Semin. Nephrol. 2010; 30: 234-254Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 4Misharin A.V. Morales-Nebreda L. Reyfman P.A. Cuda C.M. Walter J.M. McQuattie-Pimentel A.C. Chen C.-I. Anekalla K.R. Joshi N. Williams K.J.N. Abdala-Valencia H. Yacoub T.J. Chi M. Chiu S. Gonzalez-Gonzalez F.J. et al.Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span.J. Exp. Med. 2017; 214: 2387-2404Crossref PubMed Scopus (382) Google Scholar, 5Woollard K.J. Geissmann F. Monocytes in atherosclerosis: Subsets and functions.Nat. Rev. Cardiol. 2010; 7: 77-86Crossref PubMed Scopus (595) Google Scholar, 6Katschke K.J. Rottman J.B. Ruth J.H. Qin S. Wu L. LaRosa G. Ponath P. Park C.C. Pope R.M. Koch A.E. Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis.Arthritis Rheum. 2001; 44: 1022-1032Crossref PubMed Scopus (248) Google Scholar, 7Zuroff L. Daley D. Black K.L. Koronyo-Hamaoui M. Clearance of cerebral Aβ in Alzheimer's disease: Reassessing the role of microglia and monocytes.Cell Mol. Life Sci. 2017; 74: 2167-2201Crossref PubMed Scopus (117) Google Scholar, M. A. J. H. D. S. N. A. et of monocyte recruitment in PubMed Google Scholar). METTL3 shown to in inflammatory in Y. D. L. METTL3 regulates differentiation and inflammatory signaling and J. Mol. Sci. 2019; Scopus Google Scholar), cells Z. R. B. METTL3 regulates of the inflammatory in human Mol. Med. PubMed Scopus Google Scholar), and cells Zhao J. H. Z. F. H. Y. fatty acid through suppressing inflammation Immunol. 2019; PubMed Scopus Google Scholar), is known the role of METTL3 in monocyte In this study, we that inflammatory METTL3 mitochondrial and inflammatory in monocytes suppressing PGC-1α. have identified a new mechanism METTL3 in monocyte inflammation, in which METTL3 with PGC-1α mRNA to its m6A YTHDF2 m6A modification to PGC-1α mRNA of PGC-1α by METTL3 to the expression of mitochondrial respiratory chain and thereby ATP production and accumulation in inflammatory monocytes These data may provide new into the role of METTL3-dependent m6A modification of PGC-1α mRNA in monocyte inflammatory and in understanding of pathogenesis of monocyte-macrophage The of m6A modification are and by the of m6A binding and the of modified Y. The of RNA methylation in and 2019; 9: PubMed Scopus Google Scholar, Z. A. Y. D. Y. M. G. B. C. regulation of RNA PubMed Scopus Google Scholar). The m6A and are in the and have different by with and with and YTHDF2 to with regulation of mRNA YTHDF2 mRNA m6A in the the and the to promote m6A RNA Z. A. Y. D. Y. M. G. B. C. regulation of RNA PubMed Scopus Google Scholar). The of YTHDF2 to m6A the the to RNA in the and the to the RNA H. Zhao Y. J. Zhang Y. H. M. J. Wu L. YTHDF2 RNA through recruitment of the 7: PubMed Scopus Google Scholar). with mRNA YTHDF2 m6A methylation and PGC-1α mRNA degradation, thereby decreasing PGC-1α mRNA and protein In contrast, METTL3 or YTHDF2 increased mRNA and protein data that the METTL3 on PGC-1α expression the m6A function of may also play a role in this the the m6A methylation of PGC-1α mRNA and the expression of PGC-1α Huang N. Yang M. D. H. H. J. Qin J. Chen H. H. is for by regulating mitochondria 2017; PubMed Scopus Google Scholar). such, may in PGC-1α mRNA PGC-1α regulates in mitochondrial biogenesis and energy metabolism by with a of coactivator (e.g., and transcription and and receptor Metabolic control of mitochondrial biogenesis through the PGC-1 family 2011; PubMed Scopus Google Scholar). Dysregulation of PGC-1α may to mitochondrial and mitochondrial oxidative cycle and fatty acid oxidation (14Dorn G.W. Kitsis R.N. The mitochondrial dynamism-mitophagy-cell death interactome: Multiple roles performed by members of a mitochondrial molecular ensemble.Circ. Res. 2015; 116: 167-182Crossref PubMed Scopus (106) Google Scholar, Metabolic control of mitochondrial biogenesis through the PGC-1 family 2011; PubMed Scopus Google Scholar). In this study, METTL3 methylation to for YTHDF2 of the expression of PGC-1α, and which to mitochondrial in monocytes. The mitochondrial may to of and in monocytes during acute is a of the the cytochrome c cytochrome subunit of to the cytochrome The respiratory to the of the is for activation of with in the cytochrome c of and Full Text PDF PubMed Google Scholar). PGC-1α can with to activate the Metabolic control of mitochondrial biogenesis through the PGC-1 family 2011; PubMed Scopus Google Scholar). is of the of mitochondrial and the protein can expression of and Yang H. H. R. Zhang C. N. Wu S. S. M. Wu J. B. A. Chen R. by on mitochondrial Natl. Acad. Sci. U. S. A. 2017; PubMed Scopus Google Scholar). The of the transcription binding by in the binding for and PGC-1α has been identified as a coactivator of P. Wu Z. Park R. M. Spiegelman B.M. coactivator of receptors to Full Text Full Text PDF PubMed Scopus Google and as well as with a variety of transcription and S. F. H. W. in the pathogenesis of 2 2006; PubMed Scopus Google Scholar). is to that a of PGC-1α, the relationship between the molecules is these that and in inflammatory monocytes PGC-1α by METTL3 with of PGC-1α, and and oxidative phosphorylation for ATP thereby mitochondrial ATP and inflammation G. S. L. R. M. M. L. C. C. B. C. et al.Mitochondrial regulates respiratory activity of Full Text Full Text PDF PubMed Scopus Google Scholar). In we demonstrated that METTL3 mitochondrial and inflammatory during inflammation in monocytes. METTL3 m6A methylation of PGC-1α mRNA, as of METTL3 monocyte inflammation and mitochondrial function These data may provide new insights into the role of METTL3-dependent m6A modification of PGC-1α mRNA in monocyte inflammation and provide into the pathogenesis of monocyte-macrophage cells in Park with and with at in with and cells in modified with and with at in with and endothelial cells of human by and in with between 2 and for the For following the for METTL3 PGC-1α YTHDF2 or a control following the for For monocyte inflammation cells with for and for the of human myeloid cells data in the of METTL3 the and the performed R.M. The Mol. 2015; PubMed Scopus Google Scholar). the cells with on and in The The at for in an and the for of protein by protein and in for of to and with in and at for 2 with The with at with for with in at for with the by system and and and cellular RNA and with and a of and the levels of different performed the in the as a for of RNA the The in transcription ATP, RNA 2 RNA to performed in a for and RNA and the of the of PGC-1α mRNA between the and of a The and into the and of a cells in cells with cells with of the and for an and with a system following the to the as to RNA by RNA in the of of with of cell for at with and the by of cells and in a 2 and The cell with METTL3 at for by the with and in and by RNA cells with and to to of through the of PGC-1α 2 to cell of the at and The mRNA levels at different by in with and with for and to for and For ATP levels, an ATP following the For cell cells in a at a density of 2 and in in the of for at to cellular the of cells and in and to with the For cell cells in a at a density of 2 and with for the the cells with for the in the cellular The of at and at For cell cells in a at a density of 2 and with for the the cells with for mitochondria and the in the cellular by The of at and at cells into the cell at cells with METTL3 and PGC-1α for and with for The a and in and to protein by protein in In 3 well in a in and to cells with METTL3 and PGC-1α for and with for monocytes with of in to the of monocytes well in a and for in at well with and an data are as and The and of for data are the and the This The that they have of with the of this to for This by the of Z. and L. Z. and L. G. A. H. J. and J. N. Z. Z. and L. H. J. and J. N. and with and

Topics & Concepts