Lipotoxicity and mitochondrial phospholipids
Dietary fatty acids are essential components of cellular membrane phospholipids. As such, animals have evolved numerous adaptive mechanisms to maintain their phospholipid acyl tail composition, despite dietary variation and changes in nutrient abundance. One such adaptation is the safe storage of fatty acids as triglycerides in adipocytes, a cell type specialized in handling large quantities of fatty acids. However, in obesity and insulin resistance, this adaptation fails, leading to a spill-over of excess fatty acids into peripheral organs. In these organs, excess fatty acids induce numerous pathogenic insults collectively termed as lipotoxicity, which ultimately leads to the development of type 2 diabetes, non-alcoholic fatty liver disease and other obesity-related comorbidities.
Mitochondrial dysfunction is one of the hallmarks of lipotoxicity. However, the precise mechanisms that link aberrant fatty acid metabolism to mitochondrial dysfunction are unclear. Therefore, using various in vitro lipotoxicity models and genetically engineered cell lines with altered fatty acid handling, we aim to dissect changes in mitochondrial phospholipid composition during acute and chronic lipotoxic stress. Furthermore, we investigate how lipotoxicity-induced changes in mitochondrial phospholipid composition affect mitochondrial dynamics and respiration. Lastly, we aim to understand how different mitochondrial processes, such as respiration and reactive oxygen species production, affect the overall cellular phospholipid composition and cell survival during lipotoxic stress.
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