Mitochondrial genome architecture in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is associated with mitochondrial dysfunction, a decreased liver mitochondrial DNA (mtDNA) content, and impaired energy metabolism. To understand the clinical implications of mtDNA diversity in the biology of NAFLD, we applied deep-coverage whole sequencing o...

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Publicado:	2016
Materias:	fatty liver gene expression liver fibrosis mitochondrial dysfunction mitochondrial genome NASH non-alcoholic fatty liver disease cytochrome c oxidase DNA directed DNA polymerase gamma glutamine histidine mitochondrial DNA reduced nicotinamide adenine dinucleotide dehydrogenase transfer RNA adult Article body mass clinical article comparative study controlled study disease severity DNA content electron microscopy female follow up gene frequency gene locus gene sequence genetic variability heteroplasmy histopathology human human tissue immunoreactivity liver biopsy male middle aged missense mutation mitochondrial DNA replication mutation rate nonalcoholic fatty liver oxidative phosphorylation phenotype point mutation POLG gene POLG2 gene priority journal protein expression replication study sequence analysis single nucleotide polymorphism case control study genetic polymorphism genetic predisposition genetics germline mutation haplotype liver cirrhosis liver mitochondrion mutation severity of illness index Adult Case-Control Studies DNA, Mitochondrial Female Genetic Predisposition to Disease Genome, Mitochondrial Germ-Line Mutation Haplotypes Humans Liver Cirrhosis Male Middle Aged Mitochondria, Liver Mutation Mutation, Missense Non-alcoholic Fatty Liver Disease Oxidative Phosphorylation Polymorphism, Genetic Severity of Illness Index
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00223417_v240_n4_p437_Sookoian http://hdl.handle.net/20.500.12110/paper_00223417_v240_n4_p437_Sookoian
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paper:paper_00223417_v240_n4_p437_Sookoian
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spelling	paper:paper_00223417_v240_n4_p437_Sookoian2023-06-08T14:49:59Z Mitochondrial genome architecture in non-alcoholic fatty liver disease fatty liver gene expression liver fibrosis mitochondrial dysfunction mitochondrial genome NASH non-alcoholic fatty liver disease cytochrome c oxidase DNA directed DNA polymerase gamma glutamine histidine mitochondrial DNA reduced nicotinamide adenine dinucleotide dehydrogenase transfer RNA mitochondrial DNA adult Article body mass clinical article comparative study controlled study disease severity DNA content electron microscopy female follow up gene frequency gene locus gene sequence genetic variability heteroplasmy histopathology human human tissue immunoreactivity liver biopsy liver fibrosis male middle aged missense mutation mitochondrial DNA replication mitochondrial genome mutation rate nonalcoholic fatty liver oxidative phosphorylation phenotype point mutation POLG gene POLG2 gene priority journal protein expression replication study sequence analysis single nucleotide polymorphism case control study genetic polymorphism genetic predisposition genetics germline mutation haplotype liver cirrhosis liver mitochondrion mutation nonalcoholic fatty liver severity of illness index Adult Case-Control Studies DNA, Mitochondrial Female Genetic Predisposition to Disease Genome, Mitochondrial Germ-Line Mutation Haplotypes Humans Liver Cirrhosis Male Middle Aged Mitochondria, Liver Mutation Mutation, Missense Non-alcoholic Fatty Liver Disease Oxidative Phosphorylation Polymorphism, Genetic Severity of Illness Index Non-alcoholic fatty liver disease (NAFLD) is associated with mitochondrial dysfunction, a decreased liver mitochondrial DNA (mtDNA) content, and impaired energy metabolism. To understand the clinical implications of mtDNA diversity in the biology of NAFLD, we applied deep-coverage whole sequencing of the liver mitochondrial genomes. We used a multistage study design, including a discovery phase, a phenotype-oriented study to assess the mutational burden in patients with steatohepatitis at different stages of liver fibrosis, and a replication study to validate findings in loci of interest. We also assessed the potential protein-level impact of the observed mutations. To determine whether the observed changes are tissue-specific, we compared the liver and the corresponding peripheral blood entire mitochondrial genomes. The nuclear genes POLG and POLG2 (mitochondrial DNA polymerase-γ) were also sequenced. We observed that the liver mtDNA of patients with NAFLD harbours complex genomes with a significantly higher mutational (1.28-fold) rate and degree of heteroplasmy than in controls. The analysis of liver mitochondrial genomes of patients with different degrees of fibrosis revealed that the disease severity is associated with an overall 1.4-fold increase in mutation rate, including mutations in genes of the oxidative phosphorylation (OXPHOS) chain. Significant differences in gene and protein expression patterns were observed in association with the cumulative number of OXPHOS polymorphic sites. We observed a high degree of homology (∼98%) between the blood and liver mitochondrial genomes. A missense POLG p.Gln1236His variant was associated with liver mtDNA copy number. In conclusion, we have demonstrated that OXPHOS genes contain the highest number of hotspot positions associated with a more severe phenotype. The variability of the mitochondrial genomes probably originates from a common germline source; hence, it may explain a fraction of the ‘missing heritability’ of NAFLD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 2016 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00223417_v240_n4_p437_Sookoian http://hdl.handle.net/20.500.12110/paper_00223417_v240_n4_p437_Sookoian
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	fatty liver gene expression liver fibrosis mitochondrial dysfunction mitochondrial genome NASH non-alcoholic fatty liver disease cytochrome c oxidase DNA directed DNA polymerase gamma glutamine histidine mitochondrial DNA reduced nicotinamide adenine dinucleotide dehydrogenase transfer RNA mitochondrial DNA adult Article body mass clinical article comparative study controlled study disease severity DNA content electron microscopy female follow up gene frequency gene locus gene sequence genetic variability heteroplasmy histopathology human human tissue immunoreactivity liver biopsy liver fibrosis male middle aged missense mutation mitochondrial DNA replication mitochondrial genome mutation rate nonalcoholic fatty liver oxidative phosphorylation phenotype point mutation POLG gene POLG2 gene priority journal protein expression replication study sequence analysis single nucleotide polymorphism case control study genetic polymorphism genetic predisposition genetics germline mutation haplotype liver cirrhosis liver mitochondrion mutation nonalcoholic fatty liver severity of illness index Adult Case-Control Studies DNA, Mitochondrial Female Genetic Predisposition to Disease Genome, Mitochondrial Germ-Line Mutation Haplotypes Humans Liver Cirrhosis Male Middle Aged Mitochondria, Liver Mutation Mutation, Missense Non-alcoholic Fatty Liver Disease Oxidative Phosphorylation Polymorphism, Genetic Severity of Illness Index
spellingShingle	fatty liver gene expression liver fibrosis mitochondrial dysfunction mitochondrial genome NASH non-alcoholic fatty liver disease cytochrome c oxidase DNA directed DNA polymerase gamma glutamine histidine mitochondrial DNA reduced nicotinamide adenine dinucleotide dehydrogenase transfer RNA mitochondrial DNA adult Article body mass clinical article comparative study controlled study disease severity DNA content electron microscopy female follow up gene frequency gene locus gene sequence genetic variability heteroplasmy histopathology human human tissue immunoreactivity liver biopsy liver fibrosis male middle aged missense mutation mitochondrial DNA replication mitochondrial genome mutation rate nonalcoholic fatty liver oxidative phosphorylation phenotype point mutation POLG gene POLG2 gene priority journal protein expression replication study sequence analysis single nucleotide polymorphism case control study genetic polymorphism genetic predisposition genetics germline mutation haplotype liver cirrhosis liver mitochondrion mutation nonalcoholic fatty liver severity of illness index Adult Case-Control Studies DNA, Mitochondrial Female Genetic Predisposition to Disease Genome, Mitochondrial Germ-Line Mutation Haplotypes Humans Liver Cirrhosis Male Middle Aged Mitochondria, Liver Mutation Mutation, Missense Non-alcoholic Fatty Liver Disease Oxidative Phosphorylation Polymorphism, Genetic Severity of Illness Index Mitochondrial genome architecture in non-alcoholic fatty liver disease
topic_facet	fatty liver gene expression liver fibrosis mitochondrial dysfunction mitochondrial genome NASH non-alcoholic fatty liver disease cytochrome c oxidase DNA directed DNA polymerase gamma glutamine histidine mitochondrial DNA reduced nicotinamide adenine dinucleotide dehydrogenase transfer RNA mitochondrial DNA adult Article body mass clinical article comparative study controlled study disease severity DNA content electron microscopy female follow up gene frequency gene locus gene sequence genetic variability heteroplasmy histopathology human human tissue immunoreactivity liver biopsy liver fibrosis male middle aged missense mutation mitochondrial DNA replication mitochondrial genome mutation rate nonalcoholic fatty liver oxidative phosphorylation phenotype point mutation POLG gene POLG2 gene priority journal protein expression replication study sequence analysis single nucleotide polymorphism case control study genetic polymorphism genetic predisposition genetics germline mutation haplotype liver cirrhosis liver mitochondrion mutation nonalcoholic fatty liver severity of illness index Adult Case-Control Studies DNA, Mitochondrial Female Genetic Predisposition to Disease Genome, Mitochondrial Germ-Line Mutation Haplotypes Humans Liver Cirrhosis Male Middle Aged Mitochondria, Liver Mutation Mutation, Missense Non-alcoholic Fatty Liver Disease Oxidative Phosphorylation Polymorphism, Genetic Severity of Illness Index
description	Non-alcoholic fatty liver disease (NAFLD) is associated with mitochondrial dysfunction, a decreased liver mitochondrial DNA (mtDNA) content, and impaired energy metabolism. To understand the clinical implications of mtDNA diversity in the biology of NAFLD, we applied deep-coverage whole sequencing of the liver mitochondrial genomes. We used a multistage study design, including a discovery phase, a phenotype-oriented study to assess the mutational burden in patients with steatohepatitis at different stages of liver fibrosis, and a replication study to validate findings in loci of interest. We also assessed the potential protein-level impact of the observed mutations. To determine whether the observed changes are tissue-specific, we compared the liver and the corresponding peripheral blood entire mitochondrial genomes. The nuclear genes POLG and POLG2 (mitochondrial DNA polymerase-γ) were also sequenced. We observed that the liver mtDNA of patients with NAFLD harbours complex genomes with a significantly higher mutational (1.28-fold) rate and degree of heteroplasmy than in controls. The analysis of liver mitochondrial genomes of patients with different degrees of fibrosis revealed that the disease severity is associated with an overall 1.4-fold increase in mutation rate, including mutations in genes of the oxidative phosphorylation (OXPHOS) chain. Significant differences in gene and protein expression patterns were observed in association with the cumulative number of OXPHOS polymorphic sites. We observed a high degree of homology (∼98%) between the blood and liver mitochondrial genomes. A missense POLG p.Gln1236His variant was associated with liver mtDNA copy number. In conclusion, we have demonstrated that OXPHOS genes contain the highest number of hotspot positions associated with a more severe phenotype. The variability of the mitochondrial genomes probably originates from a common germline source; hence, it may explain a fraction of the ‘missing heritability’ of NAFLD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
title	Mitochondrial genome architecture in non-alcoholic fatty liver disease
title_short	Mitochondrial genome architecture in non-alcoholic fatty liver disease
title_full	Mitochondrial genome architecture in non-alcoholic fatty liver disease
title_fullStr	Mitochondrial genome architecture in non-alcoholic fatty liver disease
title_full_unstemmed	Mitochondrial genome architecture in non-alcoholic fatty liver disease
title_sort	mitochondrial genome architecture in non-alcoholic fatty liver disease
publishDate	2016
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00223417_v240_n4_p437_Sookoian http://hdl.handle.net/20.500.12110/paper_00223417_v240_n4_p437_Sookoian
_version_	1768544213557837824

Mitochondrial genome architecture in non-alcoholic fatty liver disease

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