The genetic and metabolic signature of oncocytic transformation implicates HIF1α destabilization

被引：100

作者：

Porcelli, Anna Maria ^{[2
]}

Ghelli, Anna ^{[2
]}

Ceccarelli, Claudio ^{[3
]}

Lang, Martin ^{[1
]}

Cenacchi, Giovanna ^{[3
]}

Capristo, Mariantonietta ^{[2
]}

Pennisi, Lucia Fiammetta ^{[1
]}

Morra, Isabella ^{[4
]}

Ciccarelli, Enrica ^{[5
]}

Melcarne, Antonio ^{[6
]}

Bartoletti-Stella, Anna ^{[1
]}

Salfi, Nunzio ^{[3
]}

Tallini, Giovanni ^{[7
]}

Martinuzzi, Andrea ^{[8
]}

Carelli, Valerio ^{[9
]}

Attimonelli, Marcella ^{[10
]}

Rugolo, Michela ^{[2
]}

Romeo, Giovanni ^{[1
]}

Gasparre, Giuseppe ^{[1
,10
]}

机构：

[1] Univ Bologna, Dipartimento Sci Ginecol Ostetr & Pediat Genet Me, I-40138 Bologna, Italy

[2] Univ Bologna, Dipartimento Biol Evoluzionist Sperimentale, I-40126 Bologna, Italy

[3] Policlin Univ S Orsola Malpighi, Unita Operat Anat & Istol Patol, I-40138 Bologna, Italy

[4] Az Osped OIRM S Anna, Serv Anat Patol, I-10100 Turin, Italy

[5] Osp Evangelico Valdese, Serv Endocrinol, I-10100 Turin, Italy

[6] Az Osped CTO M Adelaide, Div Neurochirurgia, I-10100 Turin, Italy

[7] Univ Bologna, Dipartimento Ematol & Sci Oncol LEA Seragnoli, I-40139 Bologna, Italy

[8] Ist Sci E Medea, I-31015 Conegliano, Italy

[9] Univ Bologna, Dipartimento Sci Neurol, I-40123 Bologna, Italy

[10] Univ Bari, Dipartimento Biochim & Biol Mol E Quagliariello, I-70126 Bari, Italy

来源：

HUMAN MOLECULAR GENETICS | 2010年 / 19卷 / 06期

关键词：

MITOCHONDRIAL-DNA MUTATIONS; HEREDITARY OPTIC NEUROPATHY; RESPIRATORY COMPLEX-I; THYROID-TUMORS; RENAL ONCOCYTOMA; POINT MUTATION; HIF PATHWAY; CELLS; MTDNA; CANCER;

D O I：

10.1093/hmg/ddp566

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 HIF1 alpha 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 HIF1 alpha 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 HIF1 alpha stabilization.

引用

页码：1019 / 1032

页数：14

共 53 条

[1] Human mtDNA site-specific variability values can act as haplogroup markers [J].