2. Academic Validation
  3. Mitochondrial glutamine import sustains electron transport chain integrity independently of glutaminolysis in cancer

Mitochondrial glutamine import sustains electron transport chain integrity independently of glutaminolysis in cancer

  • Mol Cell. 2026 Jan 8;86(1):150-165.e9. doi: 10.1016/j.molcel.2025.12.001.
Lingzhi Zhu 1,  Kuishen Wu 1,  Jianwei You 1,  Wen Mi 1,  Jie Xu 2,  Liucheng Li 1,  Fang Yang 1,  Xinyi Xia 1,  Haohang Yan 1,  Fei Li 3,  Li Chen 1,  Pingyu Liu 2,  Fuming Li 4
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Drug Clinical Trial Center, Shanghai Xuhui Central Hospital, Institute of Clinical Mass Spectrometry, Shanghai Academy of Experimental Medicine, Fudan University, Shanghai 200438, China.
  • 2 Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai 201203, China.
  • 3 Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Frontier Innovation Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 4 Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Drug Clinical Trial Center, Shanghai Xuhui Central Hospital, Institute of Clinical Mass Spectrometry, Shanghai Academy of Experimental Medicine, Fudan University, Shanghai 200438, China. Electronic address: [email protected].
PMID: 41435838 DOI: 10.1016/j.molcel.2025.12.001
Abstract

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-tRNAGln, the most limiting mitochondrial aminoacyl-tRNA in Cancer cells. Finally, deleting SLC1A5 in mice and targeting SLC1A5var in xenograft tumors inhibit Gln-mt-tRNAGln 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.

Keywords

SLC1A5var; glutamine; glutaminolysis; mitochondrial glutamine import; mitochondrial translation.

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