The mitochondrial carrier SLC25A10 regulates cancer cell growth

Abstract

Dysregulation of cell metabolism is critical for the growth properties of cancer cells. The purpose of this study was to understand the role of substrate transport across the mitochondrial membrane to sustain the metabolic shift and redox defense in cancer cells. Mitochondrial carrier SLC25A10 is up-regulated in a variety of tumors and is involved in regulating intracellular levels of reactive oxygen species. We show that knockdown of SLC25A10 in A549 cells changed the growth properties to a less malignant phenotype and casued increased glutamine dependency and sensitivity to oxidative stress. The metabolic alteration was linked to an energy metabolic shift from glycolysis to mitochondrial oxidative phosphorylation illustrated by increased expression of glutamate dehydrogenase, decreased expression of lactate dehydrogenase due to down-regulation of hypoxia inducible factor 1α. We identified effects on NADPH production linked to the growth changes observed in SLC25A10 knockdown cells, demonstrated by decreased NADPH production in cells deprived of glutamine. The contribution of SLC25A10 to reprogram cell metabolism and to regulate cell growth suggests SLC25A10 as a novel target for anti-cancer strategies.

Genetic and Epigenetic Variation across Genes Involved in Energy Metabolism and Mitochondria of Chinese Hamster Ovary Cell Lines

“…Despite the essentiality of glutamine for cellular bioenergy, an adaptive survival response of cells has been observed in glutamine‐deprived environments . Adaptations in metabolic regulatory enzymes were observed in cells sensitive to glutamine deprivation with significant changes in expression levels of glutamate dehydrogenase (GLUD1 and GLUD2) and lactate dehydrogenase (LDHA and LDHB) . In agreement with these reports associated with glutamine deprivation, we observed nonconservative mutations in glutamate dehydrogenase 1 (GLUD1—five insertions), glutathione disulfide reductase (GSR—1 stop gain SNV, one insertion), and lactate dehydrogenase A (LDHA—three insertions) genes specifically in the cells adapted to grow without glutamine (CHO‐K1 NoGln) (Table S11, Supporting Information).…”

S-adenosylhomocysteine hydrolase regulates anterior patterning inDugesia japonica

“…Although the exact mechanism of GSH transport by SLC25A10 is unclear, it suggests that AdOx-treated worms may experience oxidative stress. Interestingly, PSAT1 and SLC25A10 are overexpressed in various cancer types where they promote cell proliferation and correlate with poor prognosis [40]–[43]. Hence, upregulation of these genes in AdOx-exposed planarians may help promote cell proliferation to counteract the extensive apoptosis triggered by the inhibitor.…”

Mitochondrial carriers in inflammation induced by bacterial endotoxin and cytokines

“…The expression of SLC25A10 significantly increases by about four times in LPS-stimulated U937 cells and macrophages (Iacobazzi et al unpublished work, 2016). Although extensive and specific studies have not been performed on SLC25A10 in inflammation yet, interesting clues come from cancer cells that show a metabolic condition similar to that of inflammation (Zhou et al, 2015). Similar to the situation in inflammatory U937 cells and macrophages, SLC25A10 is up-regulated in cancer cells (Zhou et al, 2015).…”

“…Although extensive and specific studies have not been performed on SLC25A10 in inflammation yet, interesting clues come from cancer cells that show a metabolic condition similar to that of inflammation (Zhou et al, 2015). Similar to the situation in inflammatory U937 cells and macrophages, SLC25A10 is up-regulated in cancer cells (Zhou et al, 2015). Down-regulation of its expression changes the growth properties to a less malignant phenotype in A549 cells, which is likely due to increased glutamine dependency and sensitivity to oxidative stress.…”

“…Down-regulation of its expression changes the growth properties to a less malignant phenotype in A549 cells, which is likely due to increased glutamine dependency and sensitivity to oxidative stress. As a metabolic consequence of SLC25A10 down-regulation, there is a shift from glycolysis to OXPHOS, which is observed in reduced level of lactate dehydrogenase and HIF-1α, as well as increased glutamate dehydrogenase expression (Zhou et al, 2015).…”