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It has been proposed that mitochondrial unfolded-protein response (UPR\n                    <jats:sup>mt<\/jats:sup>\n                    ) activation improves mitochondrial function in the liver. Growing evidence demonstrates that physical exercise effectively prevents and treats MASLD. However, the effects of exercise on UPR\n                    <jats:sup>mt<\/jats:sup>\n                    activation in the liver are unknown. Thus, we investigated the impact of aerobic training on the mechanisms involved in mitochondrial quality control in the liver in a mouse model of obesity. Liver transcript data from a genetic reference panel of BXD isogenic mice revealed a negative correlation between UPR\n                    <jats:sup>mt<\/jats:sup>\n                    -related genes and hepatic triacylglycerol content. In addition, the liver UPR\n                    <jats:sup>mt<\/jats:sup>\n                    markers were strongly associated with several mitochondrial-related genes in the hepatic tissue of BXD mice and humans. Notably, 4 weeks of aerobic exercise strongly impacted the liver metabolism, preventing intrahepatic lipid accumulation in HFD-fed mice. Physical exercise boosted the NAD-biosynthesis pathway, elicited the mitonuclear protein imbalance, stimulated the protein content of UPR\n                    <jats:sup>mt<\/jats:sup>\n                    -markers, including CLpP, Lonp1, and Yme1L1, and improved the mitochondrial proteostasis and function in the liver in HFD-fed mice. Thus, our findings link the mitonuclear protein imbalance and UPR\n                    <jats:sup>mt<\/jats:sup>\n                    activation in the liver to mitochondrial proteostasis and MASLD prevention in response to physical exercise.\n                  <\/jats:p>","DOI":"10.1007\/s13105-026-01229-4","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:57:45Z","timestamp":1788271065000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exercise elicits mitonuclear protein imbalance and UPRmt in the liver of mice with obesity"],"prefix":"10.1007","volume":"82","author":[{"given":"Matheus Biscaro","family":"Rocha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izabela Monteiro","family":"de Araujo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saulo Gabriel do Nascimento Della","family":"Coleta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scylas J. 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