Abstract
Background: Maintaining a proper balance between saturated and unsaturated fatty acids in membrane phospholipids is essential for normal cellular function. The evolutionarily conserved transmembrane protein AdipoR2 plays a central role in this homeostatic process. While the detrimental effects of saturated fatty acids on cells have been previously documented, the associated ultrastructural changes remain less investigated. Methods: Here, we used transmission electron microscopy to study the consequences of silencing AdipoR2 in the presence or absence of fatty acid supplements. Results: We found that exposure of human cells to palmitic acid (PA)—the most abundant saturated fatty acid in the human body—disrupts the ultrastructure of cytoplasmic membranes and mitochondrial cristae. PA exposure also induces distinctive blebbing between the inner and outer membranes of the nuclear envelope. These membrane abnormalities are exacerbated by AdipoR2 silencing and are partially prevented by supplementation with oleic acid (OA), an unsaturated fatty acid. Furthermore, we observed ectopic localization of the mitophagy marker PINK1 and the fatty acid metabolism enzyme ACSL1 to closely apposed ER membranes, a structure that forms exclusively in PA-treated cells. Conclusions: Together, these findings reveal that exogenous PA triggers significant membrane defects, worsened in the absence of AdipoR2, and alters protein distribution within the cell. Supplementary Information: The online version contains supplementary material available at 10.1186/s12944-025-02804-2.