NIK promotes metabolic adaptation of glioblastoma cells to bioenergetic stress.
Brain Neoplasms
/ enzymology
Cell Line, Tumor
Dynamins
/ genetics
Energy Metabolism
Gene Expression Regulation, Neoplastic
Glioblastoma
/ enzymology
Humans
Mitochondria
/ enzymology
Mitochondrial Dynamics
Mitochondrial Membranes
/ enzymology
Phosphorylation
Protein Serine-Threonine Kinases
/ genetics
Tumor Microenvironment
NF-kappaB-Inducing Kinase
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
15 03 2021
15 03 2021
Historique:
received:
07
07
2020
accepted:
28
12
2020
revised:
22
12
2020
entrez:
16
3
2021
pubmed:
17
3
2021
medline:
14
9
2021
Statut:
epublish
Résumé
Cancers, including glioblastoma multiforme (GBM), undergo coordinated reprogramming of metabolic pathways that control glycolysis and oxidative phosphorylation (OXPHOS) to promote tumor growth in diverse tumor microenvironments. Adaptation to limited nutrient availability in the microenvironment is associated with remodeling of mitochondrial morphology and bioenergetic capacity. We recently demonstrated that NF-κB-inducing kinase (NIK) regulates mitochondrial morphology to promote GBM cell invasion. Here, we show that NIK is recruited to the outer membrane of dividing mitochondria with the master fission regulator, Dynamin-related protein1 (DRP1). Moreover, glucose deprivation-mediated metabolic shift to OXPHOS increases fission and mitochondrial localization of both NIK and DRP1. NIK deficiency results in decreased mitochondrial respiration, ATP production, and spare respiratory capacity (SRC), a critical measure of mitochondrial fitness. Although IκB kinase α and β (IKKα/β) and NIK are required for OXPHOS in high glucose media, only NIK is required to increase SRC under glucose deprivation. Consistent with an IKK-independent role for NIK in regulating metabolism, we show that NIK phosphorylates DRP1-S616 in vitro and in vivo. Notably, a constitutively active DRP1-S616E mutant rescues oxidative metabolism, invasiveness, and tumorigenic potential in NIK
Identifiants
pubmed: 33723235
doi: 10.1038/s41419-020-03383-z
pii: 10.1038/s41419-020-03383-z
pmc: PMC7960998
doi:
Substances chimiques
Protein Serine-Threonine Kinases
EC 2.7.11.1
DNM1L protein, human
EC 3.6.5.5
Dynamins
EC 3.6.5.5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
271Subventions
Organisme : NINDS NIH HHS
ID : R01 NS082554
Pays : United States
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