title: A mutation threshold distinguishes the antitumorigenic effects of the mitochondrial gene MTND1, an oncojanus function.
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.
authors.affiliation: Dipartimento di Scienze Ginecologiche, Ostetriche e Pediatriche, Genetica Medica, Università di Bologna, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gasparre
authors.forename: Ivana
authors.initials: I
authors.lastname: Kurelac
authors.forename: Mariantonietta
authors.initials: M
authors.lastname: Capristo
authors.forename: Luisa
authors.initials: L
authors.lastname: Iommarini
authors.forename: Anna
authors.initials: A
authors.lastname: Ghelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceccarelli
authors.forename: Giordano
authors.initials: G
authors.lastname: Nicoletti
authors.forename: Patrizia
authors.initials: P
authors.lastname: Nanni
authors.forename: Carla
authors.initials: C
authors.lastname: De Giovanni
authors.forename: Katia
authors.initials: K
authors.lastname: Scotlandi
authors.forename: Christine M
authors.initials: CM
authors.lastname: Betts
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Lollini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romeo
authors.forename: Michela
authors.initials: M
authors.lastname: Rugolo
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Porcelli
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D042967:Electron Transport Complex I / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D050259:Genes, Mitochondrial; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics*; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D019802:Succinic Acid / Q000378:metabolism
chemical_list: D042967:Electron Transport Complex I; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D009245:NADH Dehydrogenase; D019802:Succinic Acid; C515075:NADH dehydrogenase subunit 1, human