{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:30Z","timestamp":1787028570710,"version":"build-2736575974"},"reference-count":46,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, projected to affect 55% globally by 2040. Up to one-third of NAFLD patients develop non-alcoholic steatohepatitis (NASH), with 40% progressing to fibrosis. However, there are currently few reliable tools to predict disease progression. Impaired mitochondrial dynamics, characterized by dysregulated fission, fusion, and mitophagy, have emerged as key events in NAFLD pathophysiology, contributing to hepatocyte death and inflammation. This study explored the transition from steatosis to NASH through transcriptomic analyses, including data from patients with steatosis and those with NASH at different fibrosis stages. By identifying a transcriptomic signature associated with disease progression, the study revealed increased expression of genes involved in mitochondrial dynamics in NASH compared to steatosis and during NASH-related fibrosis. Histological analyses highlighted the central role of Dynamin-related protein 1 (Drp1), a dynamin GTPase essential for mitochondrial fission and mitophagy. In human liver biopsies, Drp1 expression progressively increased from NAFLD to NASH and NASH-related fibrosis and cirrhosis, predominantly in Kupffer cells. These finding suggest Drp1 is a potential driver of the transition to more severe liver damage, making it a promising biomarker for NASH development and progression and a potential therapeutic target in metabolic disorders.<\/jats:p>","DOI":"10.3390\/ijms26157373","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T14:00:41Z","timestamp":1753884041000},"page":"7373","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Analysis of the Mitochondrial Dynamics in NAFLD: Drp1 as a Marker of Inflammation and Fibrosis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3103-1294","authenticated-orcid":false,"given":"Ma\u00ebl","family":"Padelli","sequence":"first","affiliation":[{"name":"Service de Biochimie et Oncog\u00e9n\u00e9tique, H\u00f4pital Paul Brousse, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Universit\u00e9 Paris Saclay, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyne","family":"Hamelin","sequence":"additional","affiliation":[{"name":"Service de Biochimie et Oncog\u00e9n\u00e9tique, H\u00f4pital Paul Brousse, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Universit\u00e9 Paris Saclay, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7679-2524","authenticated-orcid":false,"given":"Christophe","family":"Desterke","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de M\u00e9decine du Kremlin Bic\u00eatre, Universit\u00e9 Paris-Saclay, INSERM UMRS-1310, 94276 Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6122-2542","authenticated-orcid":false,"given":"Myl\u00e8ne","family":"Sebagh","sequence":"additional","affiliation":[{"name":"Laboratoire d\u2019Anatomopathologie, H\u00f4pital Paul Brousse, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), 94800 Villejuif, France"},{"name":"UMR-S 1193, Inserm, Physiopathog\u00e9n\u00e8se et Traitement des Maladies du Foie, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Saffroy","sequence":"additional","affiliation":[{"name":"Service de Biochimie et Oncog\u00e9n\u00e9tique, H\u00f4pital Paul Brousse, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Universit\u00e9 Paris Saclay, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio Garcia","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Service de Biochimie et Oncog\u00e9n\u00e9tique, H\u00f4pital Paul Brousse, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Universit\u00e9 Paris Saclay, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3149-8617","authenticated-orcid":false,"given":"Audrey","family":"Coilly","sequence":"additional","affiliation":[{"name":"UMR-S 1193, Inserm, Physiopathog\u00e9n\u00e8se et Traitement des Maladies du Foie, 94800 Villejuif, France"},{"name":"Centre H\u00e9patobiliaire, H\u00f4pital Paul Brousse, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Universit\u00e9 Paris Saclay, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Charles","family":"Duclos-Vall\u00e9e","sequence":"additional","affiliation":[{"name":"UMR-S 1193, Inserm, Physiopathog\u00e9n\u00e8se et Traitement des Maladies du Foie, 94800 Villejuif, France"},{"name":"Centre H\u00e9patobiliaire, H\u00f4pital Paul Brousse, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Universit\u00e9 Paris Saclay, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Samuel","sequence":"additional","affiliation":[{"name":"UMR-S 1193, Inserm, Physiopathog\u00e9n\u00e8se et Traitement des Maladies du Foie, 94800 Villejuif, France"},{"name":"Centre H\u00e9patobiliaire, H\u00f4pital Paul Brousse, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Universit\u00e9 Paris Saclay, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoinette","family":"Lemoine","sequence":"additional","affiliation":[{"name":"Service de Biochimie et Oncog\u00e9n\u00e9tique, H\u00f4pital Paul Brousse, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Universit\u00e9 Paris Saclay, 94800 Villejuif, France"},{"name":"UMR-S 1193, Inserm, Physiopathog\u00e9n\u00e8se et Traitement des Maladies du Foie, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Pouwels, S., Sakran, N., Graham, Y., Leal, A., Pintar, T., Yang, W., Kassir, R., Singhal, R., Mahawar, K., and Ramnarain, D. (2022). Non-alcoholic fatty liver disease (NAFLD): A review of pathophysiology, clinical management and effects of weight loss. BMC Endocr. Disord., 22.","DOI":"10.1186\/s12902-022-00980-1"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"g4596","DOI":"10.1136\/bmj.g4596","article-title":"Non-alcoholic fatty liver disease","volume":"349","author":"Sattar","year":"2014","journal-title":"BMJ"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9","DOI":"10.4103\/ijmr.IJMR_1456_17","article-title":"Non-alcoholic fatty liver disease associated with hepatocellular carcinoma: An increasing concern","volume":"149","author":"Dhamija","year":"2019","journal-title":"Indian J. Med. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1093\/cvr\/cvad095","article-title":"Non-alcoholic fatty liver disease: Pathophysiological concepts and treatment options","volume":"119","author":"Grander","year":"2023","journal-title":"Cardiovasc. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sasaki, A., Nitta, H., Otsuka, K., Umemura, A., Baba, S., Obuchi, T., and Wakabayashi, G. (2014). Bariatric surgery and non-alcoholic Fatty liver disease: Current and potential future treatments. Front. Endocrinol., 5.","DOI":"10.3389\/fendo.2014.00164"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4","DOI":"10.21037\/tgh-20-125","article-title":"Mitochondrial dysfunction in nonalcoholic fatty liver disease and alcohol related liver disease","volume":"6","author":"Prasun","year":"2021","journal-title":"Transl. Gastroenterol. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6467","DOI":"10.18632\/aging.102972","article-title":"Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease","volume":"12","author":"Li","year":"2020","journal-title":"Aging"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/s41392-024-01839-8","article-title":"Mitochondrial dysfunction: Mechanisms and advances in therapy","volume":"9","author":"Zong","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.beem.2012.05.003","article-title":"Cellular and molecular mechanisms of mitochondrial function","volume":"26","author":"Osellame","year":"2012","journal-title":"Best. Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Chen, S., Li, Q., Shi, H., Li, F., Duan, Y., and Guo, Q. (2024). New insights into the role of mitochondrial dynamics in oxidative stress-induced diseases. Biomed. Pharmacother., 178.","DOI":"10.1016\/j.biopha.2024.117084"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Park, J., Lee, J., and Choi, C. (2011). Mitochondrial network determines intracellular ROS dynamics and sensitivity to oxidative stress through switching inter-mitochondrial messengers. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023211"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"841","DOI":"10.3350\/cmh.2022.0239","article-title":"Forecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical bayesian approach","volume":"28","author":"Le","year":"2022","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.2337\/dc14-1239","article-title":"Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: Guidelines for referral in NAFLD","volume":"38","author":"Bazick","year":"2015","journal-title":"Diabetes Care"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1146\/annurev-pathmechdis-012419-032711","article-title":"Mitochondrial dynamics and its involvement in disease","volume":"15","author":"Chan","year":"2020","journal-title":"Annu. Rev. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1196\/annals.1427.030","article-title":"Impairing the mitochondrial fission and fusion balance: A new mechanism of neurodegeneration","volume":"1147","author":"Knott","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1113\/JP271301","article-title":"Mitochondrial dynamics, mitophagy and cardiovascular disease","volume":"594","author":"Pennanen","year":"2016","journal-title":"J. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"154708","DOI":"10.1016\/j.metabol.2021.154708","article-title":"Mitochondrial dynamics and nonalcoholic fatty liver disease (NAFLD): New perspectives for a fairy-tale ending?","volume":"117","author":"Longo","year":"2021","journal-title":"Metabolism"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.molcel.2016.02.019","article-title":"Mitochondria\u2014Judges and executioners of cell death sentences","volume":"61","author":"Bhola","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.yexcr.2009.12.008","article-title":"Synergistic effect of cAMP and palmitate in promoting altered mitochondrial function and cell death in HepG2 cells","volume":"316","author":"Zhang","year":"2010","journal-title":"Exp. Cell Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"G632","DOI":"10.1152\/ajpgi.00182.2014","article-title":"Decreasing mitochondrial fission alleviates hepatic steatosis in a murine model of nonalcoholic fatty liver disease","volume":"307","author":"Galloway","year":"2014","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.2337\/db11-1640","article-title":"Transgenic control of mitochondrial fission induces mitochondrial uncoupling and relieves diabetic oxidative stress","volume":"61","author":"Galloway","year":"2012","journal-title":"Diabetes"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.bbrc.2019.04.069","article-title":"IDH2 protects against nonalcoholic steatohepatitis by alleviating dyslipidemia regulated by oxidative stress","volume":"514","author":"Gong","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4192","DOI":"10.7150\/thno.21400","article-title":"Pro-inflammatory CXCR3 impairs mitochondrial function in experimental non-alcoholic steatohepatitis","volume":"7","author":"Du","year":"2017","journal-title":"Theranostics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/j.cell.2019.04.010","article-title":"Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease","volume":"177","author":"Vives","year":"2019","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5523","DOI":"10.1073\/pnas.1108220109","article-title":"Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis","volume":"109","author":"Sorianello","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1007\/s12032-010-9779-6","article-title":"Pro-apoptotic and anti-proliferative effects of mitofusin-2 via Bax signaling in hepatocellular carcinoma cells","volume":"29","author":"Wang","year":"2012","journal-title":"Med. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"17190","DOI":"10.1074\/jbc.M212754200","article-title":"Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity","volume":"278","author":"Bach","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zerihun, M., Sukumaran, S., and Qvit, N. (2023). The Drp1-mediated mitochondrial fission protein interactome as an emerging core player in mitochondrial dynamics and cardiovascular disease therapy. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065785"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.cell.2017.08.041","article-title":"Mitochondrial fission promotes the continued clearance of apoptotic cells by macrophages","volume":"171","author":"Wang","year":"2017","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.2147\/JIR.S302944","article-title":"CTRP9 enhances efferocytosis in macrophages via MAPK\/Drp1-mediated mitochondrial fission and AdipoR1-induced immunometabolism","volume":"14","author":"Song","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1378\/chest.129.6.1673","article-title":"Burying the dead: The impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease","volume":"129","author":"Vandivier","year":"2006","journal-title":"Chest"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/ni.3253","article-title":"Phagocytosis of apoptotic cells in homeostasis","volume":"16","author":"Arandjelovic","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Wei, J., Liu, Z., Huang, X., Sun, M., Lai, W., Chen, Z., Wu, J., Chen, Y., and Guo, X. (2022). STING signaling sensing of DRP1-dependent mtDNA release in kupffer cells contributes to lipopolysaccharide-induced liver injury in mice. Redox Biol., 54.","DOI":"10.1016\/j.redox.2022.102367"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.devcel.2017.02.020","article-title":"The putative Drp1 inhibitor mdivi-1 is a reversible mitochondrial complex I inhibitor that modulates reactive oxygen species","volume":"40","author":"Bordt","year":"2017","journal-title":"Dev. Cell"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Elbadawy, M., Tanabe, K., Yamamoto, H., Ishihara, Y., Mochizuki, M., Abugomaa, A., Yamawaki, H., Kaneda, M., Usui, T., and Sasaki, K. (2023). Evaluation of the efficacy of mitochondrial fission inhibitor (Mdivi-1) using non-alcoholic steatohepatitis (NASH) liver organoids. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1243258"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.cmet.2019.11.013","article-title":"Macrophage MerTK promotes liver fibrosis in nonalcoholic steatohepatitis","volume":"31","author":"Cai","year":"2020","journal-title":"Cell Metab."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Nishida, Y., Nawaz, A., Hecht, K., and Tobe, K. (2021). Astaxanthin as a novel mitochondrial regulator: A new aspect of carotenoids, beyond antioxidants. Nutrients, 14.","DOI":"10.3390\/nu14010107"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.cmet.2013.07.004","article-title":"DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery","volume":"18","author":"Ahrens","year":"2013","journal-title":"Cell Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1002\/hep.26661","article-title":"Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease","volume":"59","author":"Moylan","year":"2014","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.1093\/bioinformatics\/bti394","article-title":"MADE4: An R package for multivariate analysis of gene expression data","volume":"21","author":"Culhane","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1093\/bioinformatics\/btn615","article-title":"AmiGO: Online access to ontology and annotation data","volume":"25","author":"Carbon","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5116","DOI":"10.1073\/pnas.091062498","article-title":"Significance analysis of microarrays applied to the ionizing radiation response","volume":"98","author":"Tusher","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Gaujoux, R., and Seoighe, C. (2010). A flexible R package for nonnegative matrix factorization. BMC Bioinform., 11.","DOI":"10.1186\/1471-2105-11-367"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1023\/A:1010933404324","article-title":"Random Forests","volume":"45","author":"Breiman","year":"2001","journal-title":"Mach. Learn."},{"key":"ref_46","first-page":"1","article-title":"FactoMineR: An R package for multivariate analysis","volume":"25","author":"Josse","year":"2008","journal-title":"J. Stat. Softw."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7373\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:19:08Z","timestamp":1760033948000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7373"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,30]]},"references-count":46,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26157373"],"URL":"https:\/\/doi.org\/10.3390\/ijms26157373","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,30]]}}}