Related Experiment Video
Updated: Jun 24, 2026
Revealing the Ferroptotic Phenotype of Medulloblastoma
Published on: March 15, 2024
NDUFA4L2 acts as a mitochondrial checkpoint against ferroptosis in hypoxic clear cell renal cell carcinoma
Xin Sun1, Qirui Zhou2, Yayun Wu3
1Department of Urology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.
Abstract:
This study aimed to define the functional role of the HIF-1α target gene NDUFA4L2 in clear cell renal cell carcinoma (ccRCC), specifically its regulation of mitochondrial function and the ferroptosis cell death pathway. Through TCGA data analysis and in vitro and in vivo models, we confirmed that HIF-1α induces NDUFA4L2 expression and mitochondrial localization. Using shRNA-mediated knockdown combined with rescue experiments employing the ferroptosis inhibitor ferrostatin-1 and the mitochondrial antioxidant mitoTEMPO, we demonstrated that silencing NDUFA4L2 triggered mitochondrial lipid peroxidation, altered mitochondrial ultrastructure, and suppressed proliferation via a mitochondria-associated ferroptotic mechanism. Mechanistically, NDUFA4L2 functioned parallel to Lactate Dehydrogenase B (LDHB); their genetic or pharmacological co-inhibition synergistically enhanced ferroptosis and suppressed cell viability in vitro and tumor growth in vivo, associated with elevated ferroptosis markers (PTGS2, 4-HNE). Furthermore, NDUFA4L2 knockdown sensitized tumors to radiotherapy by amplifying ferroptotic cell death. In conclusion, NDUFA4L2 is a critical suppressor of mitochondria-associated ferroptosis in ccRCC, acting cooperatively with LDHB to maintain redox homeostasis, and targeting the NDUFA4L2/LDHB axis represents a promising therapeutic strategy, particularly in combination with radiotherapy.
Insights
NDUFA4L2 suppresses ferroptosis in clear cell renal cell carcinoma (ccRCC). Its inhibition, alongside LDHB, enhances ferroptosis and sensitizes ccRCC tumors to radiotherapy, offering a novel therapeutic strategy.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Clear cell renal cell carcinoma (ccRCC) pathogenesis involves complex regulatory pathways.
- Mitochondrial dysfunction and ferroptosis are emerging hallmarks of cancer.
- Hypoxia-inducible factor 1-alpha (HIF-1α) plays a critical role in ccRCC progression.
Purpose of the Study:
- To elucidate the role of HIF-1α target gene NDUFA4L2 in ccRCC.
- To investigate NDUFA4L2's regulation of mitochondrial function and ferroptosis.
- To explore the therapeutic potential of targeting NDUFA4L2 in ccRCC.
Main Methods:
- Analysis of TCGA data for NDUFA4L2 expression in ccRCC.
- In vitro and in vivo ccRCC models utilizing shRNA-mediated knockdown and rescue experiments.
- Pharmacological inhibition using ferrostatin-1 (ferroptosis inhibitor) and mitoTEMPO (antioxidant).
- Assessment of mitochondrial function, lipid peroxidation, ultrastructure, and cell proliferation.
Main Results:
- HIF-1α induces NDUFA4L2 expression and mitochondrial localization in ccRCC.
- NDUFA4L2 knockdown triggers mitochondrial lipid peroxidation and ferroptosis, suppressing proliferation.
- NDUFA4L2 acts parallel to LDHB; co-inhibition synergistically enhances ferroptosis and reduces tumor growth.
- NDUFA4L2 knockdown sensitizes ccRCC to radiotherapy by increasing ferroptotic cell death.
Conclusions:
- NDUFA4L2 is a key suppressor of mitochondria-associated ferroptosis in ccRCC.
- The NDUFA4L2/LDHB axis is crucial for maintaining redox homeostasis in ccRCC.
- Targeting the NDUFA4L2/LDHB axis, especially combined with radiotherapy, presents a promising therapeutic strategy for ccRCC.
