Due to a worldwide increase in obesity and metabolic disorders such as type 2 diabetes,
synthetic sweeteners such as aspartame are frequently used to substitute sugar in the diet. Possible
uncertainties regarding aspartame’s ability to induce oxidative stress, amongst others, has led to the
recommendation of a daily maximum dose of 40 to 50 mg per kg. To date, little is known about the
effects of this non-nutritive sweetener on cellular lipid homeostasis, which, besides elevated oxidative
stress, plays an important role in the pathogenesis of various diseases, including neurodegenerative
diseases such as Alzheimer’s disease. In the present study, treatment of the human neuroblastoma
cell line SH-SY5Y with aspartame (271.7 µM) or its three metabolites (aspartic acid, phenylalanine,
and methanol (271.7 µM)), generated after digestion of aspartame in the human intestinal tract,
resulted in significantly elevated oxidative stress associated with mitochondrial damage, which was
illustrated with reduced cardiolipin levels, increased gene expression of SOD1/2, PINK1, and FIS1,
and an increase in APF fluorescence. In addition, treatment of SH-SY5Y cells with aspartame or
aspartame metabolites led to a significant increase in triacylglycerides and phospholipids, especially
phosphatidylcholines and phosphatidylethanolamines, accompanied by an accumulation of lipid
droplets inside neuronal cells. Due to these lipid-mediating properties, the use of aspartame as a
sugar substitute should be reconsidered and the effects of aspartame on the brain metabolism should
be addressed in vivo