Exercise elicits mitonuclear protein imbalance and UPRmt in the liver of mice with obesity

Abstract

Mitochondrial dysfunction plays a critical role in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). It has been proposed that mitochondrial unfolded-protein response (UPR mt ) 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 mt 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 mt -related genes and hepatic triacylglycerol content. In addition, the liver UPR mt 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 mt -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 mt activation in the liver to mitochondrial proteostasis and MASLD prevention in response to physical exercise.

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