Mitochondrial Dysfunction Induces Hepatic Lipid Accumulation and Inflammatory Responses in mtDNA Mutator Mice

Ross, J. M.; Kim, A.; Berthod, K.; Mamede-Branca, R.; Olin, M.; Pichardo-Casas, I.; Lehtio, J.; Bjorkhem, I.; Sinclair, D. A.; Olson, L.; Coppotelli, G.

doi:10.1101/2025.04.25.650453

bioRxiv · 10.1101/2025.04.25.650453

Mitochondrial Dysfunction Induces Hepatic Lipid Accumulation and Inflammatory Responses in mtDNA Mutator Mice

Ross, J. M.·Kim, A.·Berthod, K.·Mamede-Branca, R.·Olin, M.·Pichardo-Casas, I.·Lehtio, J.·Bjorkhem, I.·Sinclair, D. A.·Olson, L.·Coppotelli, G.

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Abstract

BackgroundNon-Alcoholic Fatty Liver Disease (NAFLD), now referred to as Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), is a widespread and complex health issue characterized by the accumulation of lipids in liver cells, not linked to alcohol consumption or other known liver problems. Despite its strong association with insulin resistance and obesity, a notable proportion of lean individuals develop NAFLD, suggesting the involvement of additional factors. Mitochondrial dysfunction has emerged as a potential contributor, given its role in lipid homeostasis and the generation of reactive oxidative species (ROS). MethodsIn this study, we took advantage of the mtDNA mutator mouse model, characterized by oxidative phosphorylation deficiency due to accelerated accumulation of mitochondrial DNA (mtDNA) mutations, to investigate how mitochondrial dysfunction affects liver homeostasis triggering fat accumulation. ResultsWe found that mitochondrial dysfunction induces liver steatosis and inflammation in this mouse model at a young age, independent of obesity. Using quantitative mass spectrometry, we reveal that mitochondrial dysfunction alters the levels of multiple proteins involved in lipid metabolism, cholesterol homeostasis, and inflammation. In vitro data show a shift in cellular metabolism toward the glycolytic pathway and confirm the upregulation of inflammatory genes. These changes are associated with oxidative stress and occur independently of mtDNA molecule release into the cytoplasm. ConclusionOur findings demonstrate that liver steatosis might develop as result of mitochondrial dysfunction without obesity and insulin resistance, underscoring the importance of mitochondrial dysfunction in NAFLD development in lean individuals and providing valuable insights into the molecular mechanisms underlying this complex metabolic disorder. This mouse model offers a unique platform for further investigations aimed at unraveling the intricacies of NAFLD pathogenesis and potential therapeutic targets beyond conventional risk factors.

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Ross, J. M., Kim, A., Berthod, K., Mamede-Branca, R., Olin, M., Pichardo-Casas, I., Lehtio, J., Bjorkhem, I., Sinclair, D. A., Olson, L., Coppotelli, G.. 2025-04-28. Mitochondrial Dysfunction Induces Hepatic Lipid Accumulation and Inflammatory Responses in mtDNA Mutator Mice. https://doi.org/10.1101/2025.04.25.650453

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