The genetic and metabolic signature of oncocytic transformation implicates HIF1α destabilization

Anna Maria Porcelli, Anna Ghelli, Claudio Ceccarelli, Martin Lang, Giovanna Cenacchi, Mariantonietta Capristo, Lucia Fiammetta Pennisi, Isabella Morra, Enrica Ciccarelli, Antonio Melcarne, Anna Bartoletti-Stella, Nunzio Salfi, Giovanni Tallini, Andrea Martinuzzi, Valerio Carelli, Marcella Attimonelli, Michela Rugolo, Giovanni Romeo, Giuseppe Gasparre

Research output: Contribution to journalArticlepeer-review


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 HIF1a 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 HIF1a stabilization.

Original languageEnglish
Article numberddp566
Pages (from-to)1019-1032
Number of pages14
JournalHuman Molecular Genetics
Issue number6
Publication statusPublished - Mar 2010

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology


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