NIK/MAP3K14 IS A BIOENERGETIC STRESS SENSOR AND PROMOTER OF OXIDATIVE PHOSPHORYLATION

The control of cell metabolism is intimately linked to the size and shape of mitochondria, which varies significantly across cell types. Mitochondria can elongate (fuse) with other nearby mitochondria, or they can fragment and become smaller (fission). These alterations in mitochondrial dynamics allows cells to respond rapidly to changes in the source and quantity of sugars being used, reactive oxygen species, as well as removal of damaged mitochondria through mitophagy. Imbalances in mitochondrial dynamics underlies many human diseases, including cancer. Our lab recently demonstrated that NF-B Inducing Kinase (NIK) associates with mitochondria and promotes fission. Here, we investigate our hypothesis that NIK regulates other mitochondrial processes, such as mitochondria metabolism (OXPHOS), which is often de-regulated in cancer cells. We establish that mitochondria of human brain cancer cell lines exhibit fissioned mitochondria upon acute metabolic switch from glycolytic (glucose; high sugar) to OXPHOS-promoting (galactose) media. We further demonstrate that the metabolic stress sensor, AMP-activated protein kinase (AMPK) is consistently upregulated in NIK-/- GBM cells. Critically, we show that NIK relocates to the mitochondria under conditions of metabolic stress and that NIK-deficient glioma cells die upon nutrient switching from high glucose to galactose media. Furthermore, we present data that highlights the altered metabolic status and energy consumption of NIK-deficient cancers through LC-MS metabolomics as we mitochondrial metabolism and glycolysis assays