METTL3 boosts mitochondrial fission and induces cardiac fibrosis by enhancing LncRNA GAS5 methylation
Dysregulated mitochondrial metabolism occurs in several pathological processes characterized by cell proliferation and migration. Nonetheless, the role of mitochondrial fission is not well appreciated in cardiac fibrosis, which is accompanied by enhanced fibroblast proliferation and migration. We in...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661823001962 |
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| author | Bin Tu Kai Song Yang Zhou He Sun Zhi-Yan Liu Li-Chan Lin Ji-Fei Ding Ji-Ming Sha Yan Shi Jing-Jing Yang Rui Li Ye Zhang Jian-Yuan Zhao Hui Tao |
| author_facet | Bin Tu Kai Song Yang Zhou He Sun Zhi-Yan Liu Li-Chan Lin Ji-Fei Ding Ji-Ming Sha Yan Shi Jing-Jing Yang Rui Li Ye Zhang Jian-Yuan Zhao Hui Tao |
| author_sort | Bin Tu |
| collection | DOAJ |
| description | Dysregulated mitochondrial metabolism occurs in several pathological processes characterized by cell proliferation and migration. Nonetheless, the role of mitochondrial fission is not well appreciated in cardiac fibrosis, which is accompanied by enhanced fibroblast proliferation and migration. We investigated the causes and consequences of mitochondrial fission in cardiac fibrosis using cultured cells, animal models, and clinical samples. Increased METTL3 expression caused excessive mitochondrial fission, resulting in the proliferation and migration of cardiac fibroblasts that lead to cardiac fibrosis. Knockdown of METTL3 suppressed mitochondrial fission, inhibiting fibroblast proliferation and migration for ameliorating cardiac fibrosis. Elevated METTL3 and N6-methyladenosine (m6A) levels were associated with low expression of long non-coding RNA GAS5. Mechanistically, METTL3-mediated m6A methylation of GAS5 induced its degradation, dependent of YTHDF2. GAS5 could interact with mitochondrial fission marker Drp1 directly; overexpression of GAS5 suppressed Drp1-mediated mitochondrial fission, inhibiting cardiac fibroblast proliferation and migration. Knockdown of GAS5 produced the opposite effect. Clinically, increased METTL3 and YTHDF2 levels corresponded with decreased GAS5 expression, increased m6A mRNA content and mitochondrial fission, and increased cardiac fibrosis in human heart tissue with atrial fibrillation. We describe a novel mechanism wherein METTL3 boosts mitochondrial fission, cardiac fibroblast proliferation, and fibroblast migration: METTL3 catalyzes m6A methylation of GAS5 methylation in a YTHDF2-dependent manner. Our findings provide insight into the development of preventative measures for cardiac fibrosis. |
| first_indexed | 2024-03-12T14:21:47Z |
| format | Article |
| id | doaj.art-c34a945425634addaccb33497f1dc320 |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-12T14:21:47Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-c34a945425634addaccb33497f1dc3202023-08-19T04:31:28ZengElsevierPharmacological Research1096-11862023-08-01194106840METTL3 boosts mitochondrial fission and induces cardiac fibrosis by enhancing LncRNA GAS5 methylationBin Tu0Kai Song1Yang Zhou2He Sun3Zhi-Yan Liu4Li-Chan Lin5Ji-Fei Ding6Ji-Ming Sha7Yan Shi8Jing-Jing Yang9Rui Li10Ye Zhang11Jian-Yuan Zhao12Hui Tao13Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, ChinaDepartment of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, ChinaDepartment of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, ChinaDepartment of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, ChinaDepartment of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, ChinaDepartment of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, ChinaDepartment of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, ChinaDepartment of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, ChinaInstitute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, ChinaDepartment of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, ChinaDepartment of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; Corresponding authors.Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; Corresponding authors.Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Correspondence to: Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; Corresponding author at: Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.Dysregulated mitochondrial metabolism occurs in several pathological processes characterized by cell proliferation and migration. Nonetheless, the role of mitochondrial fission is not well appreciated in cardiac fibrosis, which is accompanied by enhanced fibroblast proliferation and migration. We investigated the causes and consequences of mitochondrial fission in cardiac fibrosis using cultured cells, animal models, and clinical samples. Increased METTL3 expression caused excessive mitochondrial fission, resulting in the proliferation and migration of cardiac fibroblasts that lead to cardiac fibrosis. Knockdown of METTL3 suppressed mitochondrial fission, inhibiting fibroblast proliferation and migration for ameliorating cardiac fibrosis. Elevated METTL3 and N6-methyladenosine (m6A) levels were associated with low expression of long non-coding RNA GAS5. Mechanistically, METTL3-mediated m6A methylation of GAS5 induced its degradation, dependent of YTHDF2. GAS5 could interact with mitochondrial fission marker Drp1 directly; overexpression of GAS5 suppressed Drp1-mediated mitochondrial fission, inhibiting cardiac fibroblast proliferation and migration. Knockdown of GAS5 produced the opposite effect. Clinically, increased METTL3 and YTHDF2 levels corresponded with decreased GAS5 expression, increased m6A mRNA content and mitochondrial fission, and increased cardiac fibrosis in human heart tissue with atrial fibrillation. We describe a novel mechanism wherein METTL3 boosts mitochondrial fission, cardiac fibroblast proliferation, and fibroblast migration: METTL3 catalyzes m6A methylation of GAS5 methylation in a YTHDF2-dependent manner. Our findings provide insight into the development of preventative measures for cardiac fibrosis.http://www.sciencedirect.com/science/article/pii/S1043661823001962Cardiac fibroblastYTHDF2M6A methylationProliferationCollagen |
| spellingShingle | Bin Tu Kai Song Yang Zhou He Sun Zhi-Yan Liu Li-Chan Lin Ji-Fei Ding Ji-Ming Sha Yan Shi Jing-Jing Yang Rui Li Ye Zhang Jian-Yuan Zhao Hui Tao METTL3 boosts mitochondrial fission and induces cardiac fibrosis by enhancing LncRNA GAS5 methylation Pharmacological Research Cardiac fibroblast YTHDF2 M6A methylation Proliferation Collagen |
| title | METTL3 boosts mitochondrial fission and induces cardiac fibrosis by enhancing LncRNA GAS5 methylation |
| title_full | METTL3 boosts mitochondrial fission and induces cardiac fibrosis by enhancing LncRNA GAS5 methylation |
| title_fullStr | METTL3 boosts mitochondrial fission and induces cardiac fibrosis by enhancing LncRNA GAS5 methylation |
| title_full_unstemmed | METTL3 boosts mitochondrial fission and induces cardiac fibrosis by enhancing LncRNA GAS5 methylation |
| title_short | METTL3 boosts mitochondrial fission and induces cardiac fibrosis by enhancing LncRNA GAS5 methylation |
| title_sort | mettl3 boosts mitochondrial fission and induces cardiac fibrosis by enhancing lncrna gas5 methylation |
| topic | Cardiac fibroblast YTHDF2 M6A methylation Proliferation Collagen |
| url | http://www.sciencedirect.com/science/article/pii/S1043661823001962 |
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