The genetic and metabolic signature of oncocytic transformation implicates HIF1α destabilization

• Published in: Human molecular genetics 2010-03, Vol.19 (6), p.1019-1032
• Main Authors: Porcelli, Anna Maria, Ghelli, Anna, Ceccarelli, Claudio, Lang, Martin, Cenacchi, Giovanna, Capristo, Mariantonietta, Pennisi, Lucia Fiammetta, Morra, Isabella, Ciccarelli, Enrica, Melcarne, Antonio, Bartoletti-Stella, Anna, Salfi, Nunzio, Tallini, Giovanni, Martinuzzi, Andrea, Carelli, Valerio, Attimonelli, Marcella, Rugolo, Michela, Romeo, Giovanni, Gasparre, Giuseppe
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Molecular and cellular biology
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddp566

We previously showed that disruptive complex I mutations in mitochondrial DNA are the main genetic hallmark of oncocytic tumors of the thyroid and kidney. We here report a high frequency of homoplasmic disruptive mutations in a large panel of oncocytic pituitary and head-and-neck tumors. The presence of such mutations implicates disassembly of respiratory complex I in vivo which in turn contributes to the inability of oncocytic tumors to stabilize HIF1α and to display pseudo-hypoxia. By utilizing transmitochondrial cytoplasmic hybrids (cybrids), we induced the shift to homoplasmy of a truncating mutation in the mitochondria-coded MTND1 gene. Such shift is associated with a profound metabolic impairment leading to the imbalance of α-ketoglutarate and succinate, the Krebs cycle metabolites which are the main responsible for HIF1α stabilization. We conclude that the main hallmarks of oncocytic transformation, namely the occurrence of homoplasmic disruptive mutations and complex I disassembly, may explain the benign nature of oncocytic neoplasms through lack of HIF1α stabilization.