The genetic and metabolic signature of oncocytic transformation implicates HIF1alpha destabilization.
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.
Porcelli
Anna Maria
AM
Dipartimento di Biologia Evoluzionistica Sperimentale, Università di Bologna, Bologna 40126, Italy.
Ghelli
Anna
A
Ceccarelli
Claudio
C
Lang
Martin
M
Cenacchi
Giovanna
G
Capristo
Mariantonietta
M
Pennisi
Lucia Fiammetta
LF
Morra
Isabella
I
Ciccarelli
Enrica
E
Melcarne
Antonio
A
Bartoletti-Stella
Anna
A
Salfi
Nunzio
N
Tallini
Giovanni
G
Martinuzzi
Andrea
A
Carelli
Valerio
V
Attimonelli
Marcella
M
Rugolo
Michela
M
Romeo
Giovanni
G
Gasparre
Giuseppe
G
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
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