Mitochondrial glutamine import sustains mitochondrial translation independent of glutaminolysis in cancer

ABSTRACT: Oxidative phosphorylation (OXPHOS) fulfills energy metabolism and biosynthesis through tricarboxylic acid (TCA) cycle and an intact electron transport chain (ETC). Mitochondrial glutamine import (MGI) replenishes TCA cycle through glutaminolysis, but its broader roles in cancer remains unclear. Here we show that MGI sustains OXPHOS independent of glutaminolysis, by maintaining ETC integrity. Exogenous glutamate availability abrogates cellular dependence on glutaminolysis but not SLC1A5var-mediated MGI. Blocking MGI elicits severe mitochondrial defects, reducing mitochondrial glucose oxidation and increasing glutamine reductive carboxylation. MGI but not glutaminolysis is essential for mitochondrial translation by enabling biogenesis of Gln-mt-tRNAGln, the most limiting mitochondrial aminoacyl-tRNA in cancer cells. Finally, deleting SLC1A5 in mice and targeting SLC1A5var in human tumors inhibit Gln-mt-tRNAGln biogenesis, mitochondrial translation and blunt tumor growth. Our findings uncover a previously unrecognized role of MGI in safeguarding mitochondrial translation independent of glutaminolysis, and inform a therapeutic option by targeting MGI to abrogate OXPHOS for cancer treatment.

ORGANISM(S): Homo Sapiens

SUBMITTER: Fuming Li  

PROVIDER: PXD069373 | iProX | Tue Sep 30 00:00:00 BST 2025

REPOSITORIES: iProX