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

Autor: Masgras I; Department of Biomedical Sciences, University of Padova, via U. Bassi 58/B, 35131, Padova, Italy. ionica.masgras@gmail.com.; Institute of Neuroscience, National Research Council, via Ugo Bassi 58/B, 35131, Padova, Italy. ionica.masgras@gmail.com., Cannino G; Department of Biomedical Sciences, University of Padova, via U. Bassi 58/B, 35131, Padova, Italy., Ciscato F; Department of Biomedical Sciences, University of Padova, via U. Bassi 58/B, 35131, Padova, Italy., Sanchez-Martin C; Department of Biomedical Sciences, University of Padova, via U. Bassi 58/B, 35131, Padova, Italy., Darvishi FB; Department of Biomedical Sciences, University of Padova, via U. Bassi 58/B, 35131, Padova, Italy.; Institute of Neuroscience, National Research Council, via Ugo Bassi 58/B, 35131, Padova, Italy., Scantamburlo F; Department of Biomedical Sciences, University of Padova, via U. Bassi 58/B, 35131, Padova, Italy., Pizzi M; General Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padova, via N. Giustiniani 2, 35128, Padova, Italy., Menga A; Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, via Orabona 4, 70125, Bari, Italy., Fregona D; Department of Chemical Sciences, University of Padova, via F. Marzolo 1, 35131, Padova, Italy., Castegna A; Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, via Orabona 4, 70125, Bari, Italy.; IBIOM-CNR, Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, via G. Amendola 122/O, 70126, Bari, Italy., Rasola A; Department of Biomedical Sciences, University of Padova, via U. Bassi 58/B, 35131, Padova, Italy. andrea.rasola@unipd.it.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2022 Oct; Vol. 29 (10), pp. 1996-2008. Date of Electronic Publication: 2022 Apr 07.
DOI: 10.1038/s41418-022-00991-4
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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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