Exercise elicits mitonuclear protein imbalance and UPRmt activation in the liver, improving mitochondrial proteostasis and preventing intrahepatic lipid accumulation in obese mice.
UPRmt-related genes showed a negative correlation with hepatic triacylglycerol content in BXD isogenic mice.
Liver UPRmt markers were strongly associated with several mitochondrial-related genes in both BXD mice and humans.
Four weeks of aerobic exercise prevented intrahepatic lipid accumulation in high-fat diet (HFD)-fed mice.
Physical exercise boosted the NAD-biosynthesis pathway in the liver of HFD-fed mice.
Aerobic exercise elicited mitonuclear protein imbalance in the liver of HFD-fed mice.
Exercise increased protein content of UPRmt markers CLpP, Lonp1, and Yme1L1 in the liver of HFD-fed mice.
Aerobic exercise improved mitochondrial proteostasis and function in the liver of HFD-fed mice.
This research suggests that exercise triggers a specific cellular stress response in the liver called the mitochondrial unfolded protein response (UPRmt), which helps repair and maintain the health of mitochondria — the energy-producing structures inside cells. In mice fed a high-fat diet to induce obesity, just four weeks of aerobic exercise activated this protective response by causing an imbalance between proteins produced inside and outside the mitochondria (called mitonuclear protein imbalance), which acts like an alarm signal that kicks off a cleanup and repair process. The exercise also boosted NAD production, a molecule essential for cellular energy metabolism, and increased the levels of key quality-control proteins (CLpP, Lonp1, and Yme1L1) in the liver. The study also found that genes related to UPRmt were negatively correlated with fat accumulation in the liver — meaning that animals with higher UPRmt activity tended to have less liver fat. This relationship held true in both mouse and human liver data, suggesting the findings may be relevant to human health. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is a growing global health problem closely linked to obesity and mitochondrial dysfunction. This research suggests that aerobic exercise may help prevent or treat fatty liver disease not just by burning calories, but by activating specific molecular repair systems within liver cells. This adds to the growing understanding of why exercise is beneficial for liver health and could eventually inform the development of treatments that mimic or enhance these effects.
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Upload Your LabsRocha M, de Araujo I, Coleta S, Junior S, Peres S, Braga R, et al.. (2026). Exercise elicits mitonuclear protein imbalance and UPRmt in the liver of mice with obesity.. Journal of physiology and biochemistry. https://doi.org/10.1007/s13105-026-01229-4