A mutation threshold distinguishes the antitumorigenic effects of the mitochondrial gene MTND1, an Oncojanus function

Giuseppe Gasparre, Ivana Kurelac, Mariantonietta Capristo, Luisa Iommarini, Anna Ghelli, Claudio Ceccarelli, Giordano Nicoletti, Patrizia Nanni, Carla De Giovanni, Katia Scotlandi, Christine M. Betts, Valerio Carelli, Pier Luigi Lollini, Giovanni Romeo, Michela Rugolo, Anna Maria Porcelli

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Abstract

The oncogenic versus suppressor roles of mitochondrial genes have long been debated. Peculiar features of mitochondrial genetics such as hetero/homoplasmy and mutation threshold are seldom taken into account in this debate. Mitochondrial DNA (mtDNA) mutations generally have been claimed to be protumorigenic, but they are also hallmarks of mostly benign oncocytic tumors wherein they help reduce adaptation to hypoxia by destabilizing hypoxia-inducible factor-1α (HIF1α). To determine the influence of a disassembling mtDNA mutation and its hetero/homoplasmy on tumorigenic and metastatic potential, we injected mice with tumor cells harboring different loads of the gene MTND1 m.3571insC. Cell cultures obtained from tumor xenografts were then analyzed to correlate energetic competence, apoptosis, α-ketoglutarate (α-KG)/succinate (SA) ratio, and HIF1α stabilization with the mutation load. A threshold level for the antitumorigenic effect of MTND1 m.3571insC mutation was defined, above which tumor growth and invasiveness were reduced significantly. Notably, HIF1α destabilization and downregulation of HIF1α-dependent genes occurred in cells and tumors lacking complex I (CI), where there was an associated imbalance of α-KG/SA despite the presence of an actual hypoxic environment. These results strongly implicate mtDNA mutations as a cause of oncocytic transformation. Thus, the antitumorigenic and antimetastatic effects of high loads of MTND1 m.3571insC, following CI disassembly, define a novel threshold-regulated class of cancer genes. We suggest these genes be termed oncojanus genes to recognize their ability to contribute either oncogenic or suppressive functions in mitochondrial settings during tumorigenesis.

Original languageEnglish
Pages (from-to)6220-6229
Number of pages10
JournalCancer Research
Volume71
Issue number19
DOIs
Publication statusPublished - Oct 1 2011

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Mitochondrial Genes
Hypoxia-Inducible Factor 1
Mutation
Mitochondrial DNA
Succinic Acid
Neoplasms
Genes
Aptitude
Neoplasm Genes
Heterografts
Mental Competency
Carcinogenesis
Down-Regulation
Cell Culture Techniques
Apoptosis
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gasparre, G., Kurelac, I., Capristo, M., Iommarini, L., Ghelli, A., Ceccarelli, C., ... Porcelli, A. M. (2011). A mutation threshold distinguishes the antitumorigenic effects of the mitochondrial gene MTND1, an Oncojanus function. Cancer Research, 71(19), 6220-6229. https://doi.org/10.1158/0008-5472.CAN-11-1042

A mutation threshold distinguishes the antitumorigenic effects of the mitochondrial gene MTND1, an Oncojanus function. / Gasparre, Giuseppe; Kurelac, Ivana; Capristo, Mariantonietta; Iommarini, Luisa; Ghelli, Anna; Ceccarelli, Claudio; Nicoletti, Giordano; Nanni, Patrizia; De Giovanni, Carla; Scotlandi, Katia; Betts, Christine M.; Carelli, Valerio; Lollini, Pier Luigi; Romeo, Giovanni; Rugolo, Michela; Porcelli, Anna Maria.

In: Cancer Research, Vol. 71, No. 19, 01.10.2011, p. 6220-6229.

Research output: Contribution to journalArticle

Gasparre, G, Kurelac, I, Capristo, M, Iommarini, L, Ghelli, A, Ceccarelli, C, Nicoletti, G, Nanni, P, De Giovanni, C, Scotlandi, K, Betts, CM, Carelli, V, Lollini, PL, Romeo, G, Rugolo, M & Porcelli, AM 2011, 'A mutation threshold distinguishes the antitumorigenic effects of the mitochondrial gene MTND1, an Oncojanus function', Cancer Research, vol. 71, no. 19, pp. 6220-6229. https://doi.org/10.1158/0008-5472.CAN-11-1042
Gasparre, Giuseppe ; Kurelac, Ivana ; Capristo, Mariantonietta ; Iommarini, Luisa ; Ghelli, Anna ; Ceccarelli, Claudio ; Nicoletti, Giordano ; Nanni, Patrizia ; De Giovanni, Carla ; Scotlandi, Katia ; Betts, Christine M. ; Carelli, Valerio ; Lollini, Pier Luigi ; Romeo, Giovanni ; Rugolo, Michela ; Porcelli, Anna Maria. / A mutation threshold distinguishes the antitumorigenic effects of the mitochondrial gene MTND1, an Oncojanus function. In: Cancer Research. 2011 ; Vol. 71, No. 19. pp. 6220-6229.
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AU - Ghelli, Anna

AU - Ceccarelli, Claudio

AU - Nicoletti, Giordano

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AU - De Giovanni, Carla

AU - Scotlandi, Katia

AU - Betts, Christine M.

AU - Carelli, Valerio

AU - Lollini, Pier Luigi

AU - Romeo, Giovanni

AU - Rugolo, Michela

AU - Porcelli, Anna Maria

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