Tumor growth of neurofibromin-deficient cells is driven by decreased respiration and hampered by NAD+and SIRT3

Autor: Masgras, Ionica, Cannino, Giuseppe, Ciscato, Francesco, Sanchez-Martin, Carlos, Darvishi, Fereshteh Babaei, Scantamburlo, Francesca, Pizzi, Marco, Menga, Alessio, Fregona, Dolores, Castegna, Alessandra, Rasola, Andrea
Zdroj: Cell Death and Differentiation; October 2022, Vol. 29 Issue: 10 p1996-2008, 13p
Abstrakt: Neurofibromin loss drives neoplastic growth and a rewiring of mitochondrial metabolism. Here we report that neurofibromin ablation dampens expression and activity of NADH dehydrogenase, the respiratory chain complex I, in an ERK-dependent fashion, decreasing both respiration and intracellular NAD+. Expression of the alternative NADH dehydrogenase NDI1 raises NAD+/NADH ratio, enhances the activity of the NAD+-dependent deacetylase SIRT3 and interferes with tumorigenicity in neurofibromin-deficient cells. The antineoplastic effect of NDI1 is mimicked by administration of NAD+precursors or by rising expression of the NAD+deacetylase SIRT3 and is synergistic with ablation of the mitochondrial chaperone TRAP1, which augments succinate dehydrogenase activity further contributing to block pro-neoplastic metabolic changes. These findings shed light on bioenergetic adaptations of tumors lacking neurofibromin, linking complex I inhibition to mitochondrial NAD+/NADH unbalance and SIRT3 inhibition, as well as to down-regulation of succinate dehydrogenase. This metabolic rewiring could unveil attractive therapeutic targets for neoplasms related to neurofibromin loss.
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