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

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.

Automated summary

The loss of neurofibromin leads to the growth of tumors and a rewiring of mitochondrial metabolism. This study found that the depletion of neurofibromin inhibits the expression and activity of NADH dehydrogenase, reducing respiration and intracellular NAD(+) levels in an ERK-dependent manner. However, the expression of alternative NADH dehydrogenase NDI1 increases the NAD(+)/NADH ratio and enhances the activity of the NAD(+)-dependent deacetylase SIRT3, impairing tumorigenicity in neurofibromin-deficient cells. Additionally, mimicking the antineoplastic effect of NDI1 can be achieved through the administration of NAD(+) precursors or increasing the expression of the NAD(+) deacetylase SIRT3, and this effect is synergistic with the depletion of the mitochondrial chaperone TRAP1 and its enhancement of succinate dehydrogenase activity.