Mitochondrial DNA methylation in metabolic associated fatty liver disease
IntroductionHepatic lipid accumulation and mitochondrial dysfunction are hallmarks of metabolic associated fatty liver disease (MAFLD), yet molecular parameters underlying MAFLD progression are not well understood. Differential methylation within the mitochondrial DNA (mtDNA) has been suggested to b...
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Nutrition |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnut.2023.964337/full |
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| author | Archibold Mposhi Archibold Mposhi Fabian Cortés-Mancera Fabian Cortés-Mancera Janette Heegsma Vincent E. de Meijer Bart van de Sluis Svenja Sydor Svenja Sydor Lars P. Bechmann Lars P. Bechmann Claudia Theys Peter de Rijk Peter de Rijk Tim De Pooter Tim De Pooter Wim Vanden Berghe İkbal Agah İnce İkbal Agah İnce Klaas Nico Faber Marianne G. Rots |
| author_facet | Archibold Mposhi Archibold Mposhi Fabian Cortés-Mancera Fabian Cortés-Mancera Janette Heegsma Vincent E. de Meijer Bart van de Sluis Svenja Sydor Svenja Sydor Lars P. Bechmann Lars P. Bechmann Claudia Theys Peter de Rijk Peter de Rijk Tim De Pooter Tim De Pooter Wim Vanden Berghe İkbal Agah İnce İkbal Agah İnce Klaas Nico Faber Marianne G. Rots |
| author_sort | Archibold Mposhi |
| collection | DOAJ |
| description | IntroductionHepatic lipid accumulation and mitochondrial dysfunction are hallmarks of metabolic associated fatty liver disease (MAFLD), yet molecular parameters underlying MAFLD progression are not well understood. Differential methylation within the mitochondrial DNA (mtDNA) has been suggested to be associated with dysfunctional mitochondria, also during progression to Metabolic Steatohepatitis (MeSH). This study further investigates whether mtDNA methylation is associated with hepatic lipid accumulation and MAFLD.MethodsHepG2 cells were constructed to stably express mitochondria-targeted viral and prokaryotic cytosine DNA methyltransferases (mtM.CviPI or mtM.SssI for GpC or CpG methylation, respectively). A catalytically inactive variant (mtM.CviPI-Mut) was constructed as a control. Mouse and human patients’ samples were also investigated. mtDNA methylation was assessed by pyro- or nanopore sequencing.Results and discussionDifferentially induced mtDNA hypermethylation impaired mitochondrial gene expression and metabolic activity in HepG2-mtM.CviPI and HepG2-mtM.SssI cells and was associated with increased lipid accumulation, when compared to the controls. To test whether lipid accumulation causes mtDNA methylation, HepG2 cells were subjected to 1 or 2 weeks of fatty acid treatment, but no clear differences in mtDNA methylation were detected. In contrast, hepatic Nd6 mitochondrial gene body cytosine methylation and Nd6 gene expression were increased in mice fed a high-fat high cholesterol diet (HFC for 6 or 20 weeks), when compared to controls, while mtDNA content was unchanged. For patients with simple steatosis, a higher ND6 methylation was confirmed using Methylation Specific PCR, but no additional distinctive cytosines could be identified using pyrosequencing. This study warrants further investigation into a role for mtDNA methylation in promoting mitochondrial dysfunction and impaired lipid metabolism in MAFLD. |
| first_indexed | 2024-03-13T09:37:06Z |
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| language | English |
| last_indexed | 2024-03-13T09:37:06Z |
| publishDate | 2023-05-01 |
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| spelling | doaj.art-1824ad711d384cc69785ea814dba52922023-05-25T11:17:45ZengFrontiers Media S.A.Frontiers in Nutrition2296-861X2023-05-011010.3389/fnut.2023.964337964337Mitochondrial DNA methylation in metabolic associated fatty liver diseaseArchibold Mposhi0Archibold Mposhi1Fabian Cortés-Mancera2Fabian Cortés-Mancera3Janette Heegsma4Vincent E. de Meijer5Bart van de Sluis6Svenja Sydor7Svenja Sydor8Lars P. Bechmann9Lars P. Bechmann10Claudia Theys11Peter de Rijk12Peter de Rijk13Tim De Pooter14Tim De Pooter15Wim Vanden Berghe16İkbal Agah İnce17İkbal Agah İnce18Klaas Nico Faber19Marianne G. Rots20Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, NetherlandsDepartment of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, NetherlandsDepartment of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, NetherlandsDepartamento de Ciencias Aplicadas, Instituto Tecnológico Metropolitano, Medellín, ColombiaDepartment of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, NetherlandsDepartment of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, NetherlandsSection of Molecular Genetics, University of Groningen, University Medical Center Groningen, Groningen, NetherlandsDepartment of Internal Medicine, University Hospital Knappschaftskrankenhaus, Bochum, GermanyRuhr-University Bochum, Bochum, GermanyDepartment of Internal Medicine, University Hospital Knappschaftskrankenhaus, Bochum, GermanyRuhr-University Bochum, Bochum, GermanyDepartment of Biomedical Sciences, University of Antwerp, Antwerp, BelgiumDepartment of Biomedical Sciences, University of Antwerp, Antwerp, BelgiumNeuromics Support Facility, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerp, BelgiumDepartment of Biomedical Sciences, University of Antwerp, Antwerp, BelgiumNeuromics Support Facility, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerp, BelgiumDepartment of Biomedical Sciences, University of Antwerp, Antwerp, BelgiumDepartment of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands0Department of Medical Microbiology, School of Medicine, Acıbadem Mehmet Ali Aydınlar University, Istanbul, TürkiyeDepartment of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, NetherlandsDepartment of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, NetherlandsIntroductionHepatic lipid accumulation and mitochondrial dysfunction are hallmarks of metabolic associated fatty liver disease (MAFLD), yet molecular parameters underlying MAFLD progression are not well understood. Differential methylation within the mitochondrial DNA (mtDNA) has been suggested to be associated with dysfunctional mitochondria, also during progression to Metabolic Steatohepatitis (MeSH). This study further investigates whether mtDNA methylation is associated with hepatic lipid accumulation and MAFLD.MethodsHepG2 cells were constructed to stably express mitochondria-targeted viral and prokaryotic cytosine DNA methyltransferases (mtM.CviPI or mtM.SssI for GpC or CpG methylation, respectively). A catalytically inactive variant (mtM.CviPI-Mut) was constructed as a control. Mouse and human patients’ samples were also investigated. mtDNA methylation was assessed by pyro- or nanopore sequencing.Results and discussionDifferentially induced mtDNA hypermethylation impaired mitochondrial gene expression and metabolic activity in HepG2-mtM.CviPI and HepG2-mtM.SssI cells and was associated with increased lipid accumulation, when compared to the controls. To test whether lipid accumulation causes mtDNA methylation, HepG2 cells were subjected to 1 or 2 weeks of fatty acid treatment, but no clear differences in mtDNA methylation were detected. In contrast, hepatic Nd6 mitochondrial gene body cytosine methylation and Nd6 gene expression were increased in mice fed a high-fat high cholesterol diet (HFC for 6 or 20 weeks), when compared to controls, while mtDNA content was unchanged. For patients with simple steatosis, a higher ND6 methylation was confirmed using Methylation Specific PCR, but no additional distinctive cytosines could be identified using pyrosequencing. This study warrants further investigation into a role for mtDNA methylation in promoting mitochondrial dysfunction and impaired lipid metabolism in MAFLD.https://www.frontiersin.org/articles/10.3389/fnut.2023.964337/fullliver steatosisNAFLDNASHND6mtDNA methylation |
| spellingShingle | Archibold Mposhi Archibold Mposhi Fabian Cortés-Mancera Fabian Cortés-Mancera Janette Heegsma Vincent E. de Meijer Bart van de Sluis Svenja Sydor Svenja Sydor Lars P. Bechmann Lars P. Bechmann Claudia Theys Peter de Rijk Peter de Rijk Tim De Pooter Tim De Pooter Wim Vanden Berghe İkbal Agah İnce İkbal Agah İnce Klaas Nico Faber Marianne G. Rots Mitochondrial DNA methylation in metabolic associated fatty liver disease Frontiers in Nutrition liver steatosis NAFLD NASH ND6 mtDNA methylation |
| title | Mitochondrial DNA methylation in metabolic associated fatty liver disease |
| title_full | Mitochondrial DNA methylation in metabolic associated fatty liver disease |
| title_fullStr | Mitochondrial DNA methylation in metabolic associated fatty liver disease |
| title_full_unstemmed | Mitochondrial DNA methylation in metabolic associated fatty liver disease |
| title_short | Mitochondrial DNA methylation in metabolic associated fatty liver disease |
| title_sort | mitochondrial dna methylation in metabolic associated fatty liver disease |
| topic | liver steatosis NAFLD NASH ND6 mtDNA methylation |
| url | https://www.frontiersin.org/articles/10.3389/fnut.2023.964337/full |
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