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Rato","award":["PTDC\/BIM-MET\/4712\/2014"],"award-info":[{"award-number":["PTDC\/BIM-MET\/4712\/2014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetes mellitus type 2 (T2DM) has been associated with alterations in the male reproductive tract, especially in the epididymis. Although it is known that T2DM alters epididymal physiology, disturbing mitochondrial function and favoring oxidative stress, the mechanisms remain unknown. Sirtuin 1 (SIRT1), peroxisome proliferators-activated receptor \u03b3 coactivator 1\u03b1 (PGC-1\u03b1), and sirtuin 3 (SIRT3) are key regulators of mitochondrial function and inducers of antioxidant defenses. In this study, we hypothesized that the epididymal SIRT1\/PGC-1\u03b1\/SIRT3 axis mediates T2DM-induced epididymis dysfunction by controlling the oxidative profile. Using 7 Goto-Kakizaki (GK) rats (a non-obese model that spontaneously develops T2DM early in life), and 7 age-matched Wistar control rats, we evaluated the protein levels of SIRT1, PGC-1\u03b1, and SIRT3, as well as the expression of mitochondrial respiratory complexes. The activities of epididymal glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT) were determined, as well as the epididymal antioxidant capacity. We also evaluated protein nitration, carbonylation, and lipid peroxidation in the epididymis. The T2DM rats presented with hyperglycemia and glucose intolerance. Epididymal levels of SIRT1, PGC-1\u03b1, and SIRT3 were decreased, as well as the expression of the mitochondrial complexes II, III, and V, in the T2DM rats. We found a significant decrease in the activities of SOD, CAT, and GPx, consistent with the lower antioxidant capacity and higher protein nitration and lipid peroxidation detected in the epididymis of the T2DM rats. In sum, T2DM disrupted the epididymal SIRT1\/PGC-1\u03b1\/SIRT3 pathway, which is associated with a compromised mitochondrial function. This resulted in a decline of the antioxidant defenses and an increased oxidative damage in that tissue, which may be responsible for the impaired male reproductive function observed in diabetic men.<\/jats:p>","DOI":"10.3390\/ijms23168912","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T09:42:56Z","timestamp":1660124576000},"page":"8912","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Type 2 Diabetes Induces a Pro-Oxidative Environment in Rat Epididymis by Disrupting SIRT1\/PGC-1\u03b1\/SIRT3 Pathway"],"prefix":"10.3390","volume":"23","author":[{"given":"Ant\u00f3nia","family":"Diniz","sequence":"first","affiliation":[{"name":"CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7635-783X","authenticated-orcid":false,"given":"Marco G.","family":"Alves","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Biology, Unit for Multidisciplinary Research in Biomedicine (UMIB), Department of Microscopy, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4500-313 Porto, Portugal"},{"name":"Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, 4050-600 Porto, Portugal"},{"name":"Biotechnology of Animal and Human Reproduction (TechnoSperm), Institute of Food and Agricultural Technology, University of Girona, 17003 Girona, Spain"},{"name":"Unit of Cell Biology, Department of Biology, Faculty of Sciences, University of Girona, 17003 Girona, Spain"}]},{"given":"Emanuel","family":"Candeias","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (P\u00f3lo 1, 1st Floor), University of Coimbra, 3004-517 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0223-7867","authenticated-orcid":false,"given":"Ana I.","family":"Duarte","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (P\u00f3lo 1, 1st Floor), University of Coimbra, 3004-517 Coimbra, Portugal"},{"name":"Mitochondrial Toxicology & Experimental Therapeutics Laboratory, CNC-Center for Neuroscience and Cell Biology, UC-Biotech Building, Lot 8A, Biocant Park, 3060-197 Cantanhede, Portugal"},{"name":"Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alem\u00e3o-P\u00f3lo 3, Rua D. Francisco de Lemos, 3030-789 Coimbra, Portugal"},{"name":"CIBB-Center for Innovative Biomedicine and Biotechnology, Rua Larga, Faculty of Medicine (P\u00f3lo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5177-6747","authenticated-orcid":false,"given":"Paula I.","family":"Moreira","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (P\u00f3lo 1, 1st Floor), University of Coimbra, 3004-517 Coimbra, Portugal"},{"name":"CIBB-Center for Innovative Biomedicine and Biotechnology, Rua Larga, Faculty of Medicine (P\u00f3lo 1, 1st Floor), University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5610-8024","authenticated-orcid":false,"given":"Branca M.","family":"Silva","sequence":"additional","affiliation":[{"name":"Faculdade de Ci\u00eancias da Sa\u00fade, University of Beira Interior, Rua Marqu\u00eas d\u2019\u00c1vila e Bolama, 6201-001 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4989-5699","authenticated-orcid":false,"given":"Pedro F.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"LAQV-REQUIMTE and Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7796-2051","authenticated-orcid":false,"given":"Lu\u00eds","family":"Rato","sequence":"additional","affiliation":[{"name":"CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6201-506 Covilh\u00e3, Portugal"},{"name":"Health School of the Polytechnic Institute of Guarda, 6300-035 Guarda, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,10]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization, and International Diabetes Federation (2006). 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