ABSTRACT
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 (∨123%), maximal-respiration (∨ 95%) and spare-respiratory-capacity (∨ 83%) and ATP production (∨98%) as revealed by XF 24- Seahorse 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 ~3 days (∨ 17%), progressively reduced movement (day-2 -∨10.25%, day-5 -∨25% and day-10 -∨56%) and food intake with age (day-5-∨9% and day-10 -∨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.
Acknowledgements
The authors acknowledge the Caenorhabditis Genetics Centre (CGC), University of Minnesota funded by the National Institute of Health, USA for providing the worm strains. Divya Lodha thanks Sri Ramachandra Institute of Higher Education and Research for financial support as Chancellor fellowship. DST – FIST (SR/FST/LSI-649/2015) is gratefully acknowledged for the Extracellular flux analyzer.
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No potential conflict of interest was reported by the author(s).
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Divya Lodha
Divya Lodha and Sudarshana Rajasekaran are Senior graduate students working towards their Ph.D. One of the focus of Dr. Tamilselvan is following mitochondrial function under various scenarios. For more than 2 decades, Dr. Jamuna R. Subramaniam's research is on mechanistics and modalities to cure neurodegenerative diseases, esepcially ALS and Alzheimer disease, aging and neurotransmitter network.