title: The genetic and metabolic signature of oncocytic transformation implicates HIF1alpha destabilization.
abstract: 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 HIF1alpha 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 alpha-ketoglutarate and succinate, the Krebs cycle metabolites which are the main responsible for HIF1alpha 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 HIF1alpha stabilization.
authors.affiliation: Dipartimento di Biologia Evoluzionistica Sperimentale, Università di Bologna, Bologna 40126, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Porcelli
authors.forename: Anna
authors.initials: A
authors.lastname: Ghelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceccarelli
authors.forename: Martin
authors.initials: M
authors.lastname: Lang
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cenacchi
authors.forename: Mariantonietta
authors.initials: M
authors.lastname: Capristo
authors.forename: Lucia Fiammetta
authors.initials: LF
authors.lastname: Pennisi
authors.forename: Isabella
authors.initials: I
authors.lastname: Morra
authors.forename: Enrica
authors.initials: E
authors.lastname: Ciccarelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Melcarne
authors.forename: Anna
authors.initials: A
authors.lastname: Bartoletti-Stella
authors.forename: Nunzio
authors.initials: N
authors.lastname: Salfi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tallini
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinuzzi
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.forename: Marcella
authors.initials: M
authors.lastname: Attimonelli
authors.forename: Michela
authors.initials: M
authors.lastname: Rugolo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romeo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gasparre
mesh_terms: D015687:Cell Hypoxia; D019069:Cell Respiration; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics; D042967:Electron Transport Complex I / Q000378:metabolism; D005649:Fumarate Hydratase / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009245:NADH Dehydrogenase / Q000235:genetics; D010641:Phenotype; D014176:Protein Biosynthesis; D055550:Protein Stability; D012343:RNA, Transfer / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics; D019802:Succinic Acid / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D042967:Electron Transport Complex I; D005649:Fumarate Hydratase; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D009245:NADH Dehydrogenase; D012343:RNA, Transfer; D017382:Reactive Oxygen Species; D013385:Succinate Dehydrogenase; D019802:Succinic Acid; C515075:NADH dehydrogenase subunit 1, human