{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:56:38Z","timestamp":1790618198636,"version":"4.1.0"},"reference-count":73,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Titanium dioxide nanoparticles (TiO2-NPs) are widely used nanomaterials, but their potential systemic toxicity following chronic exposure remains a significant concern. This study investigated whether mitochondrial dysfunction represents a key mechanistic link between oxidative stress, apoptosis, and organ injury induced by TiO2-NPs. Male Wistar rats were orally exposed for 90 days to TiO2-NPs (15\u201331 nm) at doses of 215 or 500 mg\/kg body weight. Mitochondrial analyses revealed significantly impaired respiratory activity, increased membrane permeability, and mitochondrial swelling, indicating disruption of mitochondrial function and electron transport chain integrity. These alterations were accompanied by increased reactive oxygen species production; depletion of antioxidant defenses, including catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced glutathione (GSH), and glutathione S-transferase (GST); and enhanced lipid peroxidation. Increased caspase-3 activation further suggested the involvement of mitochondria-dependent apoptotic pathways. Histopathological examination confirmed significant hepatorenal damage, including hepatocellular degeneration, inflammatory infiltration, vascular alterations, and glomerular and tubular lesions. Overall, integrating mitochondrial, oxidative, apoptotic, and histopathological findings supports a mechanistic model in which mitochondrial bioenergetic dysfunction acts as a central event linking oxidative imbalance to apoptosis and tissue injury. These findings contribute to a better understanding of TiO2-NP-associated health risks and provide mechanistic insights relevant to the safer development and application of nanomaterials.<\/jats:p>","DOI":"10.3390\/ijms27198653","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:50:54Z","timestamp":1790614254000},"page":"8653","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Disruption of Mitochondrial Bioenergetics Links Oxidative Stress-Mediated Apoptosis to Hepatorenal Injury Following Sub-Chronic Exposure to Titanium Dioxide Nanoparticles"],"prefix":"10.3390","volume":"27","author":[{"given":"Sara","family":"Bouzenzana","sequence":"first","affiliation":[{"name":"Laboratory of Toxicology and Ecosystems Pathologies, Department of Living Beings, Echahid Cheikh Larbi Tebessi University, Tebessa 12002, 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