{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:17:31Z","timestamp":1788520651191,"version":"build-2803163510"},"reference-count":40,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,10,8]],"date-time":"2019-10-08T00:00:00Z","timestamp":1570492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Polish National Science Centre","award":["UMO-2018\/29\/B\/NZ1\/00589"],"award-info":[{"award-number":["UMO-2018\/29\/B\/NZ1\/00589"]}]},{"name":"European Union\u2019s Horizon 2020 Research and Innovation programme under the Marie Sk\u0142odowska-Curie Grant Agreement","award":["No. 722619 (FOIE GRAS)"],"award-info":[{"award-number":["No. 722619 (FOIE GRAS)"]}]},{"name":"European Union\u2019s Horizon 2020 Research and Innovation programme under the Marie Sk\u0142odowska-Curie Grant Agreement","award":["Grant Agreement No. 734719 (mtFOIE GRAS"],"award-info":[{"award-number":["Grant Agreement No. 734719 (mtFOIE GRAS"]}]},{"DOI":"10.13039\/501100001648","name":"European Foundation for the Study of Diabetes","doi-asserted-by":"publisher","award":["Boehringer Ingelheim European Diabetes Research Programme"],"award-info":[{"award-number":["Boehringer Ingelheim European Diabetes Research Programme"]}],"id":[{"id":"10.13039\/501100001648","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD), an increasingly prevalent and underdiagnosed disease, is postulated to be caused by hepatic fat mediated pathological mechanisms. Mitochondrial dysfunction is proposed to be involved, but it is not known whether this is a pathological driver or a consequence of NAFLD. We postulate that changes to liver mitochondrial DNA (mtDNA) are an early event that precedes mitochondrial dysfunction and irreversible liver damage. To test this hypothesis, we evaluated the impact of diet on liver steatosis, hepatic mtDNA content, and levels of key mitochondrial proteins. Liver tissues from C57BL\/6 mice fed with high fat (HF) diet (HFD) and Western diet (WD, high fat and high sugar) for 16 weeks were used. Steatosis\/fibrosis were assessed using haematoxylin and eosin (H&amp;E) Oil Red and Masson\u2019s trichome staining and collagen content. Total DNA was isolated, and mtDNA content was determined by quantifying absolute mtDNA copy number\/cell using quantitative PCR. Selected mitochondrial proteins were analysed from a proteomics screen. As expected, both HFD and WD resulted in steatosis. Mouse liver contained a high mtDNA content (3617 \u00b1 233 copies per cell), which significantly increased in HFD diet, but this increase was not functional, as indicated by changes in mitochondrial proteins. In the WD fed mice, liver dysfunction was accelerated alongside downregulation of mitochondrial oxidative phosphorylation (OXPHOS) and mtDNA replication machinery as well as upregulation of mtDNA-induced inflammatory pathways. These results demonstrate that diet induced changes in liver mtDNA can occur in a relatively short time; whether these contribute directly or indirectly to subsequent mitochondrial dysfunction and the development of NAFLD remains to be determined. If this hypothesis can be substantiated, then strategies to prevent mtDNA damage in the liver may be needed to prevent development and progression of NAFLD.<\/jats:p>","DOI":"10.3390\/cells8101222","type":"journal-article","created":{"date-parts":[[2019,10,9]],"date-time":"2019-10-09T03:14:33Z","timestamp":1570590873000},"page":"1222","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["A Diet Induced Maladaptive Increase in Hepatic Mitochondrial DNA Precedes OXPHOS Defects and May Contribute to Non-Alcoholic Fatty Liver Disease"],"prefix":"10.3390","volume":"8","author":[{"given":"Afshan N","family":"Malik","sequence":"first","affiliation":[{"name":"Department of Diabetes, School of Life Course, Faculty of Life Sciences and Medicine, King\u2019s College, London SE1 1UL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00eas C.M.","family":"Sim\u00f5es","sequence":"additional","affiliation":[{"name":"Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteur 3 Str., 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah S.","family":"Rosa","sequence":"additional","affiliation":[{"name":"Department of Diabetes, School of Life Course, Faculty of Life Sciences and Medicine, King\u2019s College, London SE1 1UL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safa","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Diabetes, School of Life Course, Faculty of Life Sciences and Medicine, King\u2019s College, London SE1 1UL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Karkucinska-Wieckowska","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Children\u2019s Memorial Health Institute, 04-730 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0789-4521","authenticated-orcid":false,"given":"Mariusz R.","family":"Wieckowski","sequence":"additional","affiliation":[{"name":"Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteur 3 Str., 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1002\/hep.28392","article-title":"Diet, weight loss, and liver health in nonalcoholic fatty liver disease: Pathophysiology, evidence, and practice","volume":"63","author":"Marchesini","year":"2016","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.bbalip.2009.10.007","article-title":"Fatty liver and lipotoxicity","volume":"1801","author":"Trauner","year":"2010","journal-title":"Biochim. et Biophys. acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4428","DOI":"10.1136\/bmj.i4428","article-title":"Non-alcoholic fatty liver disease (NAFLD): Summary of NICE guidance","volume":"354","author":"Glen","year":"2016","journal-title":"BMJ"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1172\/JCI57132","article-title":"Inflammatory links between obesity and metabolic disease","volume":"121","author":"Lumeng","year":"2011","journal-title":"J. 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