TitlePeroxynitrite supports a metabolic reprogramming in merlin-deficient Schwann cells and promotes cell survival.
Publication TypeJournal Article
Year of Publication2019
AuthorsPestoni JC, Plati SKlingeman, Camacho ODValdivia, Fuse MA, Onatunde M, Sparrow NA, Karajannis MA, Fernández-Valle C, Franco MClara
JournalJ Biol Chem
Volume294
Issue30
Pagination11354-11368
Date Published2019 07 26
ISSN1083-351X
KeywordsAnimals, Cell Survival, Cells, Cultured, Genes, Tumor Suppressor, Glutamine, Glycolysis, Humans, Mice, Mitochondria, Neurofibromatosis 2, Oxidative Phosphorylation, Oxygen Consumption, Peroxynitrous Acid, Schwann Cells
Abstract

Neurofibromatosis type 2 (NF2) is an autosomal-dominant disorder characterized by the development of bilateral vestibular schwannomas. The gene encodes the tumor suppressor merlin, and loss of merlin activity promotes tumorigenesis and causes NF2. Cellular redox signaling has been implicated in different stages of tumor development. Among reactive nitrogen species, peroxynitrite is the most powerful oxidant produced by cells. We recently showed that peroxynitrite-mediated tyrosine nitration down-regulates mitochondrial metabolism in tumor cells. However, whether peroxynitrite supports a metabolic shift that could be exploited for therapeutic development is unknown. Here, we show that vestibular schwannomas from NF2 patients and human, merlin-deficient (MD) Schwann cells have high levels of endogenous tyrosine nitration, indicating production of peroxynitrite. Furthermore, scavenging or inhibiting peroxynitrite formation significantly and selectively decreased survival of human and mouse MD-Schwann cells. Using multiple complementary methods, we also found that merlin deficiency leads to a reprogramming of energy metabolism characterized by a peroxynitrite-dependent decrease of oxidative phosphorylation and increased glycolysis and glutaminolysis. In MD-Schwann cells, scavenging of peroxynitrite increased mitochondrial oxygen consumption and membrane potential, mediated by the up-regulation of the levels and activity of mitochondrial complex IV. This increase in mitochondrial activity correlated with a decrease in the glycolytic rate and glutamine dependence. This is the first demonstration of a peroxynitrite-dependent reprogramming of energy metabolism in tumor cells. Oxidized proteins constitute a novel target for therapeutic development not only for the treatment of NF2 schwannomas but also other tumors in which peroxynitrite plays a regulatory role.

DOI10.1074/jbc.RA118.007152
Alternate JournalJ. Biol. Chem.
PubMed ID31171721
PubMed Central IDPMC6663865
Grant ListR01 NS102479 / NS / NINDS NIH HHS / United States