Loss of heterozygosity exposes germline mutations in complex I and drives Warburg metabolism in oncocytic carcinoma of the thyroid.

Summary

The authors establish an oncocytic thyroid carcinoma cell line (UT946) with profound complex I dysfunction and demonstrate that a nuclear-encoded NDUFS1 loss-of-function mutation, inherited as a recessive germline allele, becomes pathogenic via tumor LOH. Reanalysis of 91 tumors shows LOH-driven exposure of recessive germline mutations in complex I subunits as a recurrent mechanism, reinforcing selective pressure for complex I impairment and metabolic reprogramming.

Key Findings

• Established and characterized a new OCT cell line (UT946) with severe ETC complex I dysfunction and a Warburg phenotype.
• Cytoplasmic hybrid studies traced the complex I defect to a nuclear-encoded NDUFS1 loss-of-function mutation inherited as a recessive germline allele.
• Tumor LOH exposed the recessive germline mutation, causing functional complex I loss.
• Reanalysis of 91 OCT genomes showed LOH-driven exposure of recessive complex I subunit mutations as a recurrent mechanism.

Clinical Implications

Findings suggest considering germline testing of complex I genes in oncocytic thyroid carcinoma and exploring metabolic vulnerabilities (complex I dependency) for therapeutic strategies.

Limitations

• Preclinical nature limits direct clinical translation; in vivo validation not reported
• Findings are focused on oncocytic thyroid carcinoma and may not generalize to other cancers

Future Directions

Assess germline prevalence of complex I variants in OCT cohorts, evaluate therapeutic strategies exploiting complex I loss, and validate in vivo metabolic dependencies.