| First Author | Zhu L | Year | 2026 |
| Journal | Mol Cell | Volume | 86 |
| Issue | 1 | Pages | 150-165.e9 |
| PubMed ID | 41435838 | Mgi Jnum | J:378651 |
| Mgi Id | MGI:8277678 | Doi | 10.1016/j.molcel.2025.12.001 |
| Citation | Zhu L, et al. (2026) Mitochondrial glutamine import sustains electron transport chain integrity independently of glutaminolysis in cancer. Mol Cell 86(1):150-165.e9 |
| abstractText | Oxidative phosphorylation (OXPHOS) fulfills energy metabolism and biosynthesis through the tricarboxylic acid (TCA) cycle and an intact electron transport chain (ETC). Mitochondrial glutamine import (MGI) replenishes the TCA cycle through glutaminolysis, but its broader roles in cancer remain unclear. Here, we show that MGI sustains OXPHOS independently 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-tRNA(Gln), the most limiting mitochondrial aminoacyl-tRNA in cancer cells. Finally, deleting SLC1A5 in mice and targeting SLC1A5var in xenograft tumors inhibit Gln-mt-tRNA(Gln) biogenesis and mitochondrial translation and blunt tumor growth. Our findings uncover a previously unrecognized role of MGI in safeguarding ETC integrity independently of glutaminolysis and inform a therapeutic option by targeting MGI to abrogate OXPHOS for cancer treatment. |
