Detrimental effects of fructose on mitochondria in mouse motor neurons and on C. elegans healthspan

Background: Fructose-common sweetener, consumed in large quantities, is now known to be associated with various metabolic diseases. Recent reports suggest fructose's involvement in neurodegeneration, neurotoxicity, and neuroinflammation. But, its impact at cellular and subcellular level and on energy metabolism, especially, mitochondrial bioenergetics, in neurons is not known. Objectives: To study the adverse effects of high fructose in general, and on the mitochondria in a spinal cord motor neuron cell line, NSC-34, in vitro, and Caenorhabditis elegans in vivo. Methods: NSC-34 was treated with 0.5%-5% of fructose for different time periods. Fructose's effect on cell viability (MTT assay), metabolic activity (XF24 Seahorse assays) and C. elegans, chronically fed with 5% fructose and alteration in healthspan/mitochondria was monitored. Results: In NSC-34: Fructose at 4-5% elicits 60% cell death. Unlike 1%, 5% fructose (F5%) decreased mitochondrial membrane potential by 29%. Shockingly, 6hours F5% treatment almost abolished mitochondrial respiration - basal-respiration (boolean OR 123%), maximal-respiration (boolean OR 95%) and spare-respiratory-capacity (boolean OR 83%) and ATP production (boolean OR 98%) as revealed by XF 24Seahorse assays. But non - mitochondrial respiration was spared. F5% treatment for 48hrs resulted in the total shutdown of respiratory machinery including glycolysis. Chronic feeding of wildtype C.elegans to F5% throughout, shortened lifespan by similar to 3 days (boolean OR 17%), progressively reduced movement (day-2 -boolean OR 10.25%, day-5 -boolean OR 25% and day-10 -.boolean OR 56%) and food intake with age (day-5-boolean OR 9% and day-10 -boolean OR 48%) and instigated mitochondrial swelling and disarray in their arrangement in adult worms body-wall muscle cells. Conclusion: Chronic exposure to high fructose negatively impacts cell viability, mitochondrial function, basal glycolysis, and healthspan.