2. Academic Validation
  3. The non-metabolic role of MTHFD2 in regulating mitochondrial fission-dependent mitophagy via stabilizing TOP2A mRNA in glioblastoma

The non-metabolic role of MTHFD2 in regulating mitochondrial fission-dependent mitophagy via stabilizing TOP2A mRNA in glioblastoma

  • Free Radic Biol Med. 2026 Mar 16:246:93-106. doi: 10.1016/j.freeradbiomed.2026.01.016.
Zhuolin Du 1,  Xingwu Liu 2,  Yanhan Yang 1,  Xudong Min 1,  Jirui Wei 1,  Yang She 1,  Abudushalamu Abulaiti 1,  Xiayu Jin 1,  Zequn Su 1,  Shizhong Zhang 1,  Jian Liu 1,  Karrie M Kiang 3,  Gilberto Ka-Kit Leung 4,  Xiaozheng He 5,  Zhiyuan Zhu 6
Affiliations

Affiliations

  • 1 Department of Functional Neurosurgery, Neurosurgery Center, The National Key Clinical Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China.
  • 2 Neurosurgery Center, Department of Cerebrovascular Surgery, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
  • 3 Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 4 Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. Electronic address: [email protected].
  • 5 Department of Functional Neurosurgery, Neurosurgery Center, The National Key Clinical Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China. Electronic address: [email protected].
  • 6 Department of Functional Neurosurgery, Neurosurgery Center, The National Key Clinical Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China; Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. Electronic address: [email protected].
PMID: 41534569 DOI: 10.1016/j.freeradbiomed.2026.01.016
Abstract

Mitochondrial integrity is essential for tumor cell proliferation and survival. Our previous study has demonstrated the oncogenic role of the metabolic enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in glioblastoma (GBM). Given that the non-metabolic function of certain Enzymes has been reported, we aim to interrogate whether MTHFD2 has potential roles in mitochondrial integrity and dynamics, especially beyond catabolism. By using multi-faceted approaches including single-cell RNA Sequencing, mt-Keima Mitophagy flux assays, RNA immunoprecipitation Sequencing and luciferase reporter assays, we elucidated a novel, non-canonical function of MTHFD2 in stabilizing mRNA in GBM. We found that MTHFD2 was upregulated in GBM and was enriched in specific tumor subtypes cells such as ependymal-like and OPC-like cells. Knockdown of MTHFD2 profoundly promoted mitochondrial fission that triggered excessive Mitophagy and cellular Apoptosis. Mechanistically, MTHFD2 directly bound to the 3'-untranslated region (3'-UTR) of TOP2A mRNA and enhanced its stability, implying the RNA binding function of this catabolic enzyme. Overexpression of TOP2A attenuated Mitophagy and cellular Apoptosis induced by MTHFD2 depletion, indicating a vital role of MTHFD2-TOP2A axis in modulating mitochondrial integrity. Importantly, targeting MTHFD2 impeded GBM growth in orthotopic mouse models, which could be a promising therapeutic strategy. In conclusion, we proposed a non-canonical function of MTHFD2, which bound to and stabilized the mRNA of TOP2A. Targeting MTHFD2 triggered excessive Mitophagy and cell Apoptosis in GBM via destabilizing TOP2A mRNA.

Keywords

Glioblastoma; MTHFD2; Mitochondrial fission; Mitophagy; RNA-Binding protein.

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