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Intern. Med."],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and aims<\/jats:title>\n                    <jats:p>\n                      The progression of nonalcoholic fatty liver disease (NAFLD) into severe histological forms (steatohepatitis \u2013 NASH) is paralleled by the occurrence of complex molecular processes. Mitochondrial dysfunction is a hallmark feature of advanced disease. Mitochondrially encoded cytochrome B (cytochrome b,\n                      <jats:italic>MT\u2010CYB<\/jats:italic>\n                      ), a member of the oxidative phosphorylation system, is a key component of the respirasome supercomplex. Here, we hypothesized that NAFLD severity is associated with liver tissue cytochrome b mutations and damaged mitochondrial DNA (mtDNA).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We included 252 liver specimens of NAFLD patients \u2013 in whom histological disease ranged from mild to severe \u2013 which were linked to clinical and biochemical information. Tissue molecular explorations included\n                      <jats:italic>MT\u2010CYB<\/jats:italic>\n                      sequencing and analysis of differential mtDNA damage. Profiling of circulating Krebs cycle metabolites and global liver transcriptome was performed in a subsample of patients. Tissue levels of 4\u2010hydroxynonenal \u2013 a product of lipid peroxidation and 8\u2010hydroxy\u20102\u2019\u2010deoxyguanosine, a marker of oxidative damage \u2013 were measured.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared to simple steatosis, NASH is associated with a higher level of\n                      <jats:italic>MT\u2010CYB<\/jats:italic>\n                      variance, 12.1 vs. 15.6 substitutions\u2009per\u200910\n                      <jats:sup>3<\/jats:sup>\n                      \u00a0bp (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a05.5e\u201010). The burden of variants was associated with increased levels of 2\u2010hydroxyglutarate, branched\u2010chain amino acids, and glutamate, and changes in the global liver transcriptome. Liver mtDNA damage was associated with advanced disease and inflammation. NAFLD severity was associated with increased tissue levels of DNA oxidative adducts and lipid peroxyl radicals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>NASH is associated with genetic alterations of the liver cellular respirasome, including high cytochrome b variation and mtDNA damage, which may result in broad cellular effects.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/joim.13147","type":"journal-article","created":{"date-parts":[[2020,7,7]],"date-time":"2020-07-07T16:36:22Z","timestamp":1594139782000},"page":"84-96","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Liver mitochondrial DNA damage and genetic variability of Cytochrome b \u2013 a key component of the respirasome \u2013 drive the severity of fatty liver disease"],"prefix":"10.1111","volume":"289","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8234-4058","authenticated-orcid":false,"given":"C. J.","family":"Pirola","sequence":"first","affiliation":[{"name":"From the Institute of Medical Research A Lanari School of Medicine University of Buenos Aires Ciudad Aut\u00f3noma de Buenos Aires Argentina"},{"name":"Department of Molecular Genetics and Biology of Complex Diseases Institute of Medical Research (IDIM) National Scientific and Technical Research Council (CONICET) University of Buenos Aires Ciudad Aut\u00f3noma de Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Garaycoechea","sequence":"additional","affiliation":[{"name":"Department of Surgery Hospital de Alta Complejidad en Red 'El Cruce' Florencio Varela Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Flichman","sequence":"additional","affiliation":[{"name":"Department of Virology School of Pharmacy and Biochemistry University of Buenos Aires Ciudad Aut\u00f3noma de Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. O.","family":"Casta\u00f1o","sequence":"additional","affiliation":[{"name":"Liver Unit, Medicine and Surgery Department Hospital Abel Zubizarreta Ciudad Aut\u00f3noma de Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5929-5470","authenticated-orcid":false,"given":"S.","family":"Sookoian","sequence":"additional","affiliation":[{"name":"From the Institute of Medical Research A Lanari School of Medicine University of Buenos Aires Ciudad Aut\u00f3noma de Buenos Aires Argentina"},{"name":"Department of Clinical and Molecular Hepatology Institute of Medical Research (IDIM) National Scientific and Technical Research Council (CONICET) University of Buenos Aires Ciudad Aut\u00f3noma de Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,7,22]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22851"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.04.004"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2012-302962"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2001.23256"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23927"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4803"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2015.80"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2013.10.004"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.8.1777"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2017.07.021"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(04)00124-8"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-25895-7"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.115.118695"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-2555"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.07.098"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.12.4533"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1110(90)90014-3"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2014.12.011"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/0891-5849(95)02184-1"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2010.10.709"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-19216-1"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(02)00073-9"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI83885"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-019-0668-y"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2009.12.013"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199909303411404"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21710"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2012.11.015"}],"container-title":["Journal 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