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.
Highlights
Genes encoded by mitochondrial DNA have long been suspected to be actively involved in tumorigenesis when cells require high amounts of energy to grow and proliferate under few constraints
We determined the precise load of mutant mitochondrial DNA (mtDNA) by fluorescent PCR (F-PCR) in all 4 cell lines used, namely, the oncocytic thyroid carcinoma–derived XTC1 (95.5% Æ 0.35 mutation load) and ZTC1 (56.7% Æ 0.7 mutation load) as well as osteosarcoma-derived cybrids OS-93 (92.8% Æ 0.3 mutation load) and OS-85 (85.1% Æ 0.8 mutation load)
We have shown here that homoplasmy of a truncating mutation in MTND1 hampers the tumorigenic and metastatic potential of cancer cells in vivo
Summary
Genes encoded by mitochondrial DNA (mtDNA) have long been suspected to be actively involved in tumorigenesis when cells require high amounts of energy to grow and proliferate under few constraints. A question still open in cancer biology concerns the oncogenic versus the oncosuppressor behavior of metabolic genes [5, 6], which incorporate both nuclear- and mtDNA-encoded respiratory complex subunits. Enzymes such as succinate dehydrogenase and fumarate hydratase are actively involved in tumorigenesis, through imbalance of the tricarboxylic acid (TCA) cycle and stabilization of HIF1a [7, 8]. Alteration of oxidative metabolism resulting from mtDNA mutations may sustain, along with other causes, the triggering of the Warburg Effect that characterizes cancer cells and permits a shift toward glycolysis, aiding tumor progression [9, 10]. Changes in the metabolic status of cancer cells are closely related to the degree of respiratory chain dysfunction, which, in turn, depends on both mtDNA mutation type (hampering function and/or assembly of complexes) and mutation load
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
