{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:23:26Z","timestamp":1788481406097,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T00:00:00Z","timestamp":1698710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003009","name":"Science, Technology, and Innovation Funding Authority (STDF)","doi-asserted-by":"publisher","award":["33350"],"award-info":[{"award-number":["33350"]}],"id":[{"id":"10.13039\/501100003009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>(1) Background: Hepatitis C virus (HCV) infection is endemic in Egypt, with the highest prevalence rate worldwide. Sofosbuvir (SOF) is a nucleos(t)ide analog that specifically inhibits HCV replication. This study aimed to explore the possible effects of the therapeutic dose of SOF on the mitochondrial biogenesis and functions of the liver, muscle, and ovarian tissues of young normal female rats. (2) Methods: This study was conducted on 20 female Wistar rats, classified into two groups, the control group and the exposed group; the latter was orally supplemented with 4 mg\/kg\/day of SOF for 3 months. (3) Results: The exposure to SOF impairs mitochondrial biogenesis via mitochondrial DNA copy number decline and suppressed mitochondrial biogenesis-regulated parameters at mRNA and protein levels. Also, SOF suppresses the DNA polymerase \u03b3 (POLG) expression, citrate synthase activity, and mitochondrial NADH dehydrogenase subunit-5 (ND5) content, which impairs mitochondrial functions. SOF increased lipid peroxidation and oxidative DNA damage markers and decreased tissue expression of nuclear factor erythroid 2-related factor 2 (Nfe2l2). (4) Conclusions: The present findings demonstrate the adverse effects of SOF on mitochondrial biogenesis and function in different tissues of young female rats, which mostly appeared in ovarian tissues.<\/jats:p>","DOI":"10.3390\/ijms242115844","type":"journal-article","created":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T12:44:03Z","timestamp":1698756243000},"page":"15844","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Direct-Acting Antiviral Drug Modulates the Mitochondrial Biogenesis in Different Tissues of Young Female Rats"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3266-6897","authenticated-orcid":false,"given":"Hala A.","family":"Hafez","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9742-4253","authenticated-orcid":false,"given":"Ali M.","family":"Atoom","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19111, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana H. M.","family":"Khafaga","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7251-8648","authenticated-orcid":false,"given":"Sara A.","family":"Shaker","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6791-9850","authenticated-orcid":false,"given":"Maher A.","family":"Kamel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagwa M.","family":"Assem","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimaa A.","family":"Mahmoud","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/j.1478-3231.2008.01945.x","article-title":"What are the comorbidities influencing the management of patients and the response to therapy in chronic hepatitis C?","volume":"29","author":"Alberti","year":"2009","journal-title":"Liver Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"609","DOI":"10.26719\/2018.24.7.609","article-title":"Towards a hepatitis-free Egypt is this achievable","volume":"24","author":"Doss","year":"2018","journal-title":"East. Mediterr. Health J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2147\/IJGM.S119301","article-title":"Hepatitis C in Egypt\u2013past, present, and future","volume":"10","author":"Elgharably","year":"2016","journal-title":"Int. J. Gen. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.bbadis.2016.11.010","article-title":"Mitochondrial dysfunction and oxidative stress in metabolic disorders\u2014A step towards mitochondria based therapeutic strategies","volume":"1863","author":"Bhatti","year":"2017","journal-title":"Biochim. Et Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Park, J., Baruch-Torres, N., and Yin, Y.W. (2023). Structural and Molecular Basis for Mitochondrial DNA Replication and Transcription in Health and Antiviral Drug Toxicity. Molecules, 28.","DOI":"10.3390\/molecules28041796"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9696","DOI":"10.1074\/jbc.RA118.002588","article-title":"A computational approach for predicting off-target toxicity of antiviral ribonucleoside analogues to mitochondrial RNA polymerase","volume":"293","author":"Freedman","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Deval, C., Calonne, J., Coudy-Gandilhon, C., Vazeille, E., Bechet, D., Polge, C., Taillandier, D., Attaix, D., and Combaret, L. (2020). Mitophagy and mitochondria biogenesis are differentially induced in rat skeletal muscles during immobilization and\/or remobilization. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103691"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/s41420-020-00316-9","article-title":"Mitochondrial dysfunction in fibrotic diseases","volume":"6","author":"Li","year":"2020","journal-title":"Cell Death Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1128\/AAC.01922-15","article-title":"Role of mitochondrial RNA polymerase in the toxicity of nucleotide inhibitors of hepatitis C virus","volume":"60","author":"Feng","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.antiviral.2017.04.005","article-title":"Structure-activity relationship analysis of mitochondrial toxicity caused by antiviral ribonucleoside analogs","volume":"143","author":"Jin","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s12664-019-00935-w","article-title":"Effect of sofosbuvir and daclatasvir on lipid profile, glycemic control and quality of life index in chronic hepatitis C, genotype 3 patients","volume":"38","author":"Jain","year":"2019","journal-title":"Indian J. Gastroenterol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E73","DOI":"10.25011\/cim.v40i2.28198","article-title":"Liver enzyme normalization predicts success of Hepatitis C oral direct-acting antiviral treatment","volume":"40","author":"Khan","year":"2017","journal-title":"Clin. Investig. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1002\/1873-3468.14021","article-title":"Mitochondrial DNA copy number in human disease: The more the better?","volume":"595","author":"Filograna","year":"2021","journal-title":"FEBS Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"435","DOI":"10.3389\/fgene.2019.00435","article-title":"Regulation of mitochondrial biogenesis as a way for active longevity: Interaction between the Nrf2 and PGC-1\u03b1 signaling pathways","volume":"10","author":"Gureev","year":"2019","journal-title":"Front. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.bbadis.2005.04.001","article-title":"Reduced insulin-mediated citrate synthase activity in cultured skeletal muscle cells from patients with type 2 diabetes: Evidence for an intrinsic oxidative enzyme defect","volume":"1741","author":"Mogensen","year":"2005","journal-title":"Biochim. Et Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_16","first-page":"128","article-title":"Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations?","volume":"53","author":"Liolitsa","year":"2003","journal-title":"Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc."},{"key":"ref_17","first-page":"3","article-title":"Mitochondrial electron transport chain, ROS generation and uncoupling","volume":"44","author":"Zhao","year":"2019","journal-title":"Int. J. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1093\/humupd\/dmw028","article-title":"Ovarian ageing: The role of mitochondria in oocytes and follicles","volume":"22","author":"Boucret","year":"2016","journal-title":"Hum. Reprod. Update"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1631\/jzus.B0820379","article-title":"Mitochondrial functions on oocytes and preimplantation embryos","volume":"10","author":"Wang","year":"2009","journal-title":"J. Zhejiang Univ. Sci. B"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"231","DOI":"10.21451\/1984-3143-AR2018-0069","article-title":"Oocyte mitochondria: Role on fertility and disease transmission","volume":"15","author":"Chiaratti","year":"2018","journal-title":"Anim. Reprod."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e12773","DOI":"10.1111\/acel.12773","article-title":"Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice","volume":"17","author":"Foote","year":"2018","journal-title":"Aging Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"38090","DOI":"10.1038\/srep38090","article-title":"FSH protects mouse granulosa cells from oxidative damage by repressing mitophagy","volume":"6","author":"Shen","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Giovannini, C., Fornari, F., Indio, V., Trer\u00e8, D., Renzulli, M., Vasuri, F., Cescon, M., Ravaioli, M., Perrucci, A., and Astolfi, A. (2020). Direct antiviral treatments for hepatitis C virus have off-target effects of oncologic relevance in hepatocellular carcinoma. Cancers, 12.","DOI":"10.3390\/cancers12092674"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3922","DOI":"10.1016\/j.jmb.2018.07.027","article-title":"Mechanisms orchestrating mitochondrial dynamics for energy homeostasis","volume":"430","author":"Seungyoon","year":"2018","journal-title":"J. Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S0014-5793(97)01393-8","article-title":"Mitochondrial respiratory chain deficiency leads to overexpression of antioxidant enzymes","volume":"418","author":"Brambilla","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1126\/science.283.5407.1482","article-title":"Mitochondrial diseases in man and mouse","volume":"283","author":"Wallace","year":"1999","journal-title":"Science"},{"key":"ref_27","first-page":"2003","article-title":"Oxidative stress, mitochondrial damage and neurodegenerative diseases","volume":"8","author":"Guo","year":"2013","journal-title":"Neural Regen. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"R99","DOI":"10.1530\/JOE-16-0021","article-title":"PGC-1\u03b1, glucose metabolism and type 2 diabetes mellitus","volume":"229","author":"Wu","year":"2016","journal-title":"J. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"G979","DOI":"10.1152\/ajpgi.00169.2012","article-title":"PGC-1\u03b1 overexpression results in increased hepatic fatty acid oxidation with reduced triacylglycerol accumulation and secretion","volume":"303","author":"Morris","year":"2012","journal-title":"Am. J. Physiol.-Gastrointest. Liver Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.hjc.2018.08.002","article-title":"Inter-tissue expression patterns of the key metabolic biomarker PGC-1\u03b1 in severely obese individuals: Implication in obesity-induced disease","volume":"60","author":"Balampanis","year":"2019","journal-title":"Hell. J. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1053\/j.gastro.2016.09.017","article-title":"Estrogen signals through peroxisome proliferator-activated Receptor\u2212\u03b3 coactivator 1\u03b1 to reduce oxidative damage associated with diet-induced fatty liver disease","volume":"152","author":"Oropeza","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.2337\/db08-1571","article-title":"Sensitivity of lipid metabolism and insulin signaling to genetic alterations in hepatic peroxisome proliferator\u2013activated receptor-\u03b3 coactivator-1\u03b1 expression","volume":"58","author":"Estall","year":"2009","journal-title":"Diabetes"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.nutres.2013.02.003","article-title":"Gly482Ser mutation impairs the effects of peroxisome proliferator\u2013activated receptor \u03b3 coactivator-1\u03b1 on decreasing fat deposition and stimulating phosphoenolpyruvate carboxykinase expression in hepatocytes","volume":"33","author":"Chen","year":"2013","journal-title":"Nutr. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1038\/s41422-018-0078-7","article-title":"Skeletal muscle mitochondrial remodeling in exercise and diseases","volume":"28","author":"Gan","year":"2018","journal-title":"Cell Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1093\/gerona\/gln048","article-title":"Aging impairs skeletal muscle mitochondrial bioenergetic function","volume":"64","author":"Figueiredo","year":"2009","journal-title":"J. Gerontol. Ser. A Biomed. Sci. Med. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Hafez, H.A., Mahmoud, S.A., Alhmoud, J.F., Khafaga, R.H., Kamel, M.A., and Shaker, S.A. (2023). The Intergeneration Long-Lasting Consequences of Pre-Conceptional Exposure to Sofosbuvir on the Ovarian Tissues of F1 Offspring: Experimental Study on Rats. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241813675"},{"key":"ref_37","first-page":"1068","article-title":"Histological and immunohistochemical studies on the cornea and retina of sofosbuvir treated rats","volume":"4","author":"Issa","year":"2017","journal-title":"Austin J. Anat."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s10020-023-00666-x","article-title":"The pre-conception maternal exposure to Sofosbuvir affects the mitochondrial biogenesis in prenatal fetal tissues: Experimental study on rats","volume":"29","author":"Mahmoud","year":"2023","journal-title":"Mol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.2337\/dc06-0070","article-title":"New insights on the simultaneous assessment of insulin sensitivity and [beta]-cell function with the HOMA2 method","volume":"29","author":"Caumo","year":"2006","journal-title":"Diabetes Care"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/0076-6879(69)13006-2","article-title":"[2] Citrate synthase from rat liver:[EC 4.1. 3.7 Citrate oxaloacetage-lyase (CoA-acetylating)]","volume":"Volume 13","author":"Shepherd","year":"1969","journal-title":"Methods in Enzymology"},{"key":"ref_41","first-page":"384","article-title":"Enhanced mitochondrial biogenesis is associated with the ameliorative action of creatine supplementation in rat soleus and cardiac muscles","volume":"19","author":"Gowayed","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/0076-6879(90)86135-I","article-title":"[43] Malondialdehyde determination as index of lipid Peroxidation","volume":"Volume 186","author":"Draper","year":"1990","journal-title":"Methods in Enzymology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1016\/S0891-5849(01)00681-5","article-title":"Importance of complete DNA digestion in minimizing variability of 8-oxo-dG analyses","volume":"31","author":"Huang","year":"2001","journal-title":"Free Radic. Biol. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15844\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:15:16Z","timestamp":1760130916000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15844"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,31]]},"references-count":43,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242115844"],"URL":"https:\/\/doi.org\/10.3390\/ijms242115844","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,31]]}}}