DISCO TRIP - Disrupting mitochondrial complex I to trigger pseudonormoxia: an anticancer strategy

Mitochondrial DNA (mtDNA) mutations are reported to play an important role in tumor progression, although their function has been scarcely investigated especially with respect to the genetic features of mtDNA, namely hetero- versus homoplasmy and the threshold effect. Recently, we have demonstrated an anti-tumorigenic role for those mutations which contribute to respiratory complexes disassembly and, in turn, to HIF1a degradation. Noteworthy disassembling mtDNA mutations are a specific genetic hallmark of oncocytic tumors, which in fact display mostly a benign behaviour, a favourable prognosis and often lack neovascularisation. The aim of the project is to dissect the functional consequences of mtDNA mutant genotypes on the modulation of tumorigenic potential, assess the diagnostic/prognostic potential of cancer mtDNA genotypization and specifically target complex I genes to hamper tumorigenesis in vivo.