Mitochondrial lipidome exhibits relatively higher stability than cell lipidome during early neurodevelopment

Abstract Background Mitochondria play a critical role during neurodevelopment, with proliferation, differentiation, migration, and maturation requiring high energy, as cells undergo stage-specific structural modifications and high lipid turnover. While lipids are major components of cells and mitochondrial membranes, the role of lipid dynamics during critical neurodevelopmental stages remains unknown. Results Here, we used human pluripotent stem cells (PSCs) to derive neural stem cells (NSCs) and neurons and investigated dynamic changes in cellular lipids and their mitochondrial counterparts during developmental stages. A gradual increase in relative lipid content from PSCs to NSCs and from NSCs to neurons, at both the cellular and mitochondrial levels, was observed, with a relatively stable ratio of unsaturation to lipid content. Relative diacylglycerol levels demonstrated a steady, yet significant increase, accompanied by a reduction in relative triacylglycerol levels, during the development of PSCs into NSCs and then into neurons, but not in their mitochondria. Interestingly, a drastic increase in relative phosphatidylcholine levels was observed in neurons compared to PSCs and NSCs, whereas an increased phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratio was evident in both cells and their mitochondria during these developmental stages. Overall, during neurodevelopment, the cellular lipid composition demonstrated significant dynamic changes, while mitochondria exhibit a relatively stable distribution of major lipid classes, such as glycerolipids and glycerophospholipids, whereas differential lipid analyses reveal significant remodeling at the species level. Conclusions This baseline data can be used to investigate critical cellular and mitochondrial lipid perturbations in patient-derived iPSCs and their lineages in diverse neurodevelopmental disorders.