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Sookoian, S.; Flichman, D.; Scian, R.; Rohr, C.; Dopazo, H.; Gianotti, T.F.; Martino, J.S.; Castaño, G.O.; Pirola, C.J. "Mitochondrial genome architecture in non-alcoholic fatty liver disease" (2016) Journal of Pathology. 240(4):437-449
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Abstract:

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.

Registro:

Documento: Artículo
Título:Mitochondrial genome architecture in non-alcoholic fatty liver disease
Autor:Sookoian, S.; Flichman, D.; Scian, R.; Rohr, C.; Dopazo, H.; Gianotti, T.F.; Martino, J.S.; Castaño, G.O.; Pirola, C.J.
Filiación:Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires – National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
Department of Virology, School of Pharmacy and Biochemistry, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires – National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
Biomedical Genomics and Evolution Laboratory. Ecology, Genetics and Evolution Department, Faculty of Science, IEGEBA, University of Buenos Aires – National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
Department of Pathology, Hospital Diego Thompson, San Martin, Buenos Aires, Argentina
Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
Palabras clave: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
Año:2016
Volumen:240
Número:4
Página de inicio:437
Página de fin:449
DOI: http://dx.doi.org/10.1002/path.4803
Título revista:Journal of Pathology
Título revista abreviado:J. Pathol.
ISSN:00223417
CODEN:JPTLA
CAS:cytochrome c oxidase, 72841-18-0, 9001-16-5; glutamine, 56-85-9, 6899-04-3; histidine, 645-35-2, 7006-35-1, 71-00-1; reduced nicotinamide adenine dinucleotide dehydrogenase, 9027-14-9, 9032-21-7, 9079-67-8; transfer RNA, 9014-25-9; DNA, Mitochondrial
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00223417_v240_n4_p437_Sookoian

Referencias:

  • Rinella, M.E., Nonalcoholic fatty liver disease: a systematic review (2015) JAMA, 313, pp. 2263-2273
  • Brunt, E.M., Histopathology of non-alcoholic fatty liver disease (2009) Clin Liver Dis, 13, pp. 533-544
  • Bhala, N., Angulo, P., van der Poorten, D., The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study (2011) Hepatology, 54, pp. 1208-1216
  • Sookoian, S., Pirola, C.J., The genetic epidemiology of nonalcoholic fatty liver disease: toward a personalized medicine (2012) Clin Liver Dis, 16, pp. 467-485
  • Begriche, K., Massart, J., Robin, M.A., Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease (2013) Hepatology, 58, pp. 1497-1507
  • Sookoian, S., Pirola, C.J., NAFLD. Metabolic make-up of NASH: from fat and sugar to amino acids (2014) Nat Rev Gastroenterol Hepatol, 11, pp. 205-207
  • Cotter, D.G., Ercal, B., Huang, X., Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia (2014) J Clin Invest, 124, pp. 5175-5190
  • Satapati, S., Sunny, N.E., Kucejova, B., Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver (2012) J Lipid Res, 53, pp. 1080-1092
  • Befroy, D.E., Perry, R.J., Jain, N., Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy (2014) Nat Med, 20, pp. 98-102
  • Sunny, N.E., Parks, E.J., Browning, J.D., Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease (2011) Cell Metab, 14, pp. 804-810
  • Sookoian, S., Castano, G.O., Scian, R., Serum aminotransferases in nonalcoholic fatty liver disease are a signature of liver metabolic perturbations at the amino acid and Krebs cycle level (2016) Am J Clin Nutr, 103, pp. 422-434
  • Caldwell, S.H., de Freitas, L.A., Park, S.H., Intramitochondrial crystalline inclusions in nonalcoholic steatohepatitis (2009) Hepatology, 49, pp. 1888-1895
  • Garcia-Ruiz, C., Baulies, A., Mari, M., Mitochondrial dysfunction in non-alcoholic fatty liver disease and insulin resistance: cause or consequence? (2013) Free Radic Res, 47, pp. 854-868
  • Pirola, C.J., Gianotti, T.F., Burgueno, A.L., Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease (2013) Gut, 62, pp. 1356-1363
  • Sanyal, A.J., Campbell-Sargent, C., Mirshahi, F., Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities (2001) Gastroenterology, 120, pp. 1183-1192
  • Sookoian, S., Rosselli, M.S., Gemma, C., Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor gamma coactivator 1alpha promoter (2010) Hepatology, 52, pp. 1992-2000
  • Rocher, C., Taanman, J.W., Pierron, D., Influence of mitochondrial DNA level on cellular energy metabolism: implications for mitochondrial diseases (2008) J Bioenerg Biomembr, 40, pp. 59-67
  • Kauppila, J.H., Stewart, J.B., Mitochondrial DNA: radically free of free-radical driven mutations (1847) Biochim Biophys Acta, 2015, pp. 1354-1361
  • Wallace, D.C., Chalkia, D., Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease (2013) Cold Spring Harb Perspect Med, 3, p. a021220
  • Ye, K., Lu, J., Ma, F., Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals (2014) Proc Natl Acad Sci USA, 111, pp. 10654-10659
  • Stewart, J.B., Chinnery, P.F., The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease (2015) Nat Rev Genet, 16, pp. 530-542
  • Koliaki, C., Szendroedi, J., Kaul, K., Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis (2015) Cell Metab, 21, pp. 739-746
  • Taylor, R.W., Turnbull, D.M., Mitochondrial DNA mutations in human disease (2005) Nat Rev Genet, 6, pp. 389-402
  • Tuppen, H.A., Blakely, E.L., Turnbull, D.M., Mitochondrial DNA mutations and human disease (1797) Biochim Biophys Acta, 2010, pp. 113-128
  • Ovchinsky, N., Lavine, J.E., A critical appraisal of advances in pediatric nonalcoholic fatty liver disease (2012) Semin Liver Dis, 32, pp. 317-324
  • Lotowska, J.M., Sobaniec-Lotowska, M.E., Bockowska, S.B., Pediatric non-alcoholic steatohepatitis: the first report on the ultrastructure of hepatocyte mitochondria (2014) World J Gastroenterol, 20, pp. 4335-4340
  • Luoma, P.T., Luo, N., Loscher, W.N., Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome (2005) Hum Mol Genet, 14, pp. 1907-1920
  • Sookoian, S., Pirola, C.J., DNA methylation and hepatic insulin resistance and steatosis (2012) Curr Opin Clin Nutr Metab Care, 15, pp. 350-356
  • Kleiner, D.E., Brunt, E.M., Van Natta, M., Design and validation of a histological scoring system for nonalcoholic fatty liver disease (2005) Hepatology, 41, pp. 1313-1321
  • Brunt, E.M., Kleiner, D.E., Wilson, L.A., Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings (2011) Hepatology, 53, pp. 810-820
  • Pirola, C.J., Scian, R., Gianotti, T.F., Epigenetic modifications in the biology of nonalcoholic fatty liver disease: the role of DNA hydroxymethylation and TET proteins (2015) Medicine (Baltimore), 94
  • Rutledge, R.G., Sigmoidal curve-fitting redefines quantitative real-time PCR with the prospective of developing automated high-throughput applications (2004) Nucleic Acids Res, , 32
  • Gianotti, T.F., Sookoian, S., Dieuzeide, G., (2008) Obesity (Silver Spring), 16, pp. 1591-1595. , A decreased mitochondrial DNA content is related to insulin resistance in adolescents
  • Schlotter, Y.M., Veenhof, E.Z., Brinkhof, B., A GeNorm algorithm-based selection of reference genes for quantitative real-time PCR in skin biopsies of healthy dogs and dogs with atopic dermatitis (2009) Vet Immunol Immunopathol, 129, pp. 115-118
  • Ruijter, J.M., Ramakers, C., Hoogaars, W.M., Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data (2009) Nucleic Acids Res, 37
  • Bender, A., Krishnan, K.J., Morris, C.M., High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease (2006) Nat Genet, 38, pp. 515-517
  • Seneca, S., Vancampenhout, K., Van Coster, R., Analysis of the whole mitochondrial genome: translation of the Ion Torrent Personal Genome Machine system to the diagnostic bench? (2015) Eur J Hum Genet, 23, pp. 41-48
  • Sosa, M.X., Sivakumar, I.K., Maragh, S., Next-generation sequencing of human mitochondrial reference genomes uncovers high heteroplasmy frequency (2012) PLoS Comput Biol, 8
  • Sookoian, S., Castano, G.O., Burgueno, A.L., A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity (2009) J Lipid Res, 50, pp. 2111-2116
  • Bleda, M., Tarraga, J., de Maria, A., CellBase, a comprehensive collection of RESTful web services for retrieving relevant biological information from heterogeneous sources (2012) Nucleic Acids Res, pp. W609-W614. , 40

Citas:

---------- APA ----------
Sookoian, S., Flichman, D., Scian, R., Rohr, C., Dopazo, H., Gianotti, T.F., Martino, J.S.,..., Pirola, C.J. (2016) . Mitochondrial genome architecture in non-alcoholic fatty liver disease. Journal of Pathology, 240(4), 437-449.
http://dx.doi.org/10.1002/path.4803
---------- CHICAGO ----------
Sookoian, S., Flichman, D., Scian, R., Rohr, C., Dopazo, H., Gianotti, T.F., et al. "Mitochondrial genome architecture in non-alcoholic fatty liver disease" . Journal of Pathology 240, no. 4 (2016) : 437-449.
http://dx.doi.org/10.1002/path.4803
---------- MLA ----------
Sookoian, S., Flichman, D., Scian, R., Rohr, C., Dopazo, H., Gianotti, T.F., et al. "Mitochondrial genome architecture in non-alcoholic fatty liver disease" . Journal of Pathology, vol. 240, no. 4, 2016, pp. 437-449.
http://dx.doi.org/10.1002/path.4803
---------- VANCOUVER ----------
Sookoian, S., Flichman, D., Scian, R., Rohr, C., Dopazo, H., Gianotti, T.F., et al. Mitochondrial genome architecture in non-alcoholic fatty liver disease. J. Pathol. 2016;240(4):437-449.
http://dx.doi.org/10.1002/path.4803