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Updated: Mar 28, 2026
Author Spotlight: Assessing the Impact of Novel Iron Chelators on Cancer Cell Metabolism
Published on: February 23, 2024
SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery
Background:
Mutations in the Fe-S cluster-containing SDHB subunit of succinate dehydrogenase cause familial cancer syndromes. Recently the tripeptide motif L(I)YR was identified in the Fe-S recipient protein SDHB, to which the cochaperone HSC20 binds.
Methods:
In order to characterize the metabolic basis of SDH-deficient cancers we performed stable isotope-resolved metabolomics in a novel SDHB-deficient renal cell carcinoma cell line and conducted bioinformatics and biochemical screening to analyze Fe-S cluster acquisition and assembly of SDH in the presence of other cancer-causing SDHB mutations.
Results:
We found that the SDHBR46Q mutation in UOK269 cells disrupted binding of HSC20, causing rapid degradation of SDHB. In the absence of SDHB, respiration was undetectable in UOK269 cells, succinate was elevated to 351.4 ± 63.2 nmol/mg cellular protein, and glutamine became the main source of TCA cycle metabolites through reductive carboxylation.Furthermore, HIF1α, but not HIF2α, increased markedly and the cells showed a strong DNA CpG island methylatorphenotype (CIMP). Biochemical and bioinformatic screening revealed that 37% of disease-causing missense mutations in SDHB were located in either the L(I)YR Fe-S transfer motifs or in the 11 Fe-S cluster-ligating cysteines.
Conclusions:
These findings provide a conceptual framework for understanding how particular mutations disproportionately cause the loss of SDH activity, resulting in accumulation of succinate and metabolic remodeling in SDHB cancer syndromes.
Insights
Mutations in the SDHB gene disrupt iron-sulfur cluster assembly, leading to succinate accumulation and metabolic changes in familial cancer syndromes. This study clarifies how specific SDHB mutations cause loss of function and drive cancer development.
Area of Science:
- Biochemistry
- Oncology
- Metabolomics
Background:
- Mutations in the succinate dehydrogenase subunit B (SDHB) are linked to familial cancer syndromes.
- The cochaperone HSC20 binds to the L(I)YR tripeptide motif in SDHB, crucial for iron-sulfur (Fe-S) cluster acquisition.
Purpose of the Study:
- To investigate the metabolic consequences of SDHB mutations in cancer.
- To analyze the mechanisms of Fe-S cluster assembly and SDH function in the context of cancer-associated SDHB mutations.
Main Methods:
- Stable isotope-resolved metabolomics was performed on a novel SDHB-deficient renal cell carcinoma cell line.
- Bioinformatics and biochemical screening were used to analyze Fe-S cluster acquisition and SDH assembly.
Main Results:
- The SDHB R46Q mutation impaired HSC20 binding, leading to SDHB degradation and loss of cellular respiration.
- SDH deficiency resulted in elevated succinate levels and metabolic reprogramming, with glutamine becoming the primary source for the TCA cycle via reductive carboxylation.
- Hypoxia-inducible factor 1-alpha (HIF1α) increased, and a strong DNA CpG island methylator phenotype (CIMP) was observed.
- 37% of disease-causing SDHB missense mutations were located in Fe-S transfer motifs or Fe-S cluster-ligating cysteines.
Conclusions:
- Specific SDHB mutations can disproportionately impair SDH activity by disrupting Fe-S cluster assembly.
- Succinate accumulation and subsequent metabolic remodeling are key events in SDHB-deficient cancers.
- These findings offer a framework for understanding the pathogenesis of SDHB-related cancer syndromes.
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