Inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis

Cancer as a Metabolic Disease

“…Although the RTG response has been most studied in yeast, mitochondrial stress signaling is an analogous response in mammalian cells [110,111]. Expression of multiple nuclear genes controlling energy metabolism is profoundly altered following impairment in mitochondrial energy homeostasis [112,113]. Mitochondrial impairment can arise from abnormalities in mtDNA, the TCA cycle, the electron transport chain, or in the proton motive gradient (ΔΨ m ) of the inner membrane.…”

“…This mostly involves an energy transition from oxidative phosphorylation to substrate level phosphorylation. Similar systems are also expressed in mammalian cells [110][111][112][113]. Prolonged or continued activation of the retrograde response, however, can have dire consequences on nuclear genome stability and function.…”

“…In the on state, cytoplasmic Rtg2 disengages the Rtg1/Rtg-3 complex through a dephosphorylation of Rtg3 [110]. The Rtg1 and Rtg3 proteins then individually enter the nucleus where Rtg3 binds to R box sites, Rtg1 reengages Rtg3, and transcription and signaling commences for multiple energy and anti-apoptotic related genes and proteins to include MYC, TOR, p53, Ras, CREB, NFkB, and CHOP [110,112,113,[116][117][118]. The RTG response also involves the participation of multiple negative and positive regulators, which facilitate the bioenergetic transition from respiration to substrate level phosphorylation [110].…”

“…The recent studies of the Singh and the Jazwinski groups provide compelling evidence that mitochondrial dysfunction, operating largely through the RTG response (mitochondrial stress signaling), can underlie the mutator phenotype of tumor cells [71,113,115,117,138]. Chromosomal instability, expression of gene mutations, and the tumorigenic phenotype were significantly greater in human cells with mtDNA depletion than in cells with normal mtDNA.…”

Nuclear–mitochondrial genomic profiling reveals a pattern of evolution in epithelial ovarian tumor stem cells

“…It has been earlier suggested that complementation with specific mutations in nuclear genes (Singh et al, 2005) or epigenetic regulation (Feinberg et al, 2006) could be the next step required to propel a stem cell towards a tumorigenic program. To resolve this, we carried out mutational analyses CREBBP in the five clones expressing the mutant mtDNA profile, the primary tumor and ascites-derived cells and one representative clone expressing the germ line mtDNA profile, viz.…”