INhibitor of Growth (ING2) gene has been recently characterized as a tumor suppressor gene. Indeed, ING2 protein has been involved in caretaker and gatekeeper functions (apoptosis, senescence, DNA repair…) [1 Cancer Lett 2014 ;  345 (1) : 1-16

Cliquez ici pour aller à la section Références]. Interestingly, ING2 expression is frequently lost in non-small cell lung cancer (NSCLC) and is an early event in cancerogenesis [2 Lung Cancer 2010 ;  69 (2) : 180-186

Cliquez ici pour aller à la section Références]. Mitochondria dysfunctions have been largely described in cancer, notably in NSCLC where altered bioenergetics and mitochondrial DNA (mtDNA) instability promote tumorigenesis. Moreover, well-known tumor suppressor proteins are localized to mitochondria (p53, VHL). Therefore, we hypothesized that ING2 protein could translocate into the mitochondria and may be implicated in tumor suppressor functions in this organelle.

ING2 protein localization in U2OS cell line was studied by immunoelectron and immunofluorescence microscopy, and western blot after cellular fractionation. Sub-fractionation of mitochondria was performed using a digitonin treatment. Cells were treated with MitoBlock-6 or Glucose oxidase to explore respectively mitochondrial import of ING2 protein and the ING2 response to oxidative stress. MtDNA recovery from oxidative damage was evaluated by quantitative long-amplicon PCR on isolated mtDNA.

We determined the mitochondrial localization of ING2 protein. We described precisely the localization of ING2 protein in the inner mitochondrial fraction, close to the electron transport chain and mtDNA. We showed that the mitochondrial disulfide relay system is mainly responsible for ING2 mitochondrial import. Furthermore, upon oxidative stress, ING2 protein amount in the mitochondrial compartment decreased in a dose-dependent manner. However, in our model, a loss of ING2 expression had not impact on mtDNA recovery from oxidative damage.

We revealed for the first time the presence of ING2 protein in mitochondria and uncovered its import mechanism. We observed subsequent variations of the ING2 mitochondrial amount under oxidative stress. However, ING2 silencing had not impact on mtDNA stability. Finally, we hypothesize that ING2 could prevent tumorigenesis and NSCLC emergence by regulating mitochondrial functions rather than protecting mtDNA.