Cancer cells are characterized by a metabolic reprogramming involving a switch from mitochondrial respiration to aerobic glycolysis, known as the Warburg effect and by an elevated level of oxidative stress as a result of the accumulation of reactive oxygen species (ROS). While low levels of ROS activate signaling cascades, excessive levels of ROS cause cell death. Therefore, cancer cells need to develop mechanisms to maintain ROS at moderate levels. Components of the respiratory chain in the IM generate superoxide (O2) on both sides the IM;both in the matrix and in the IMS. In the matrix, SIRT3 regulates the activity of the superoxide dismutase SOD2, which converts O2 into hydrogen peroxide (H2O2). However, the expression of SIRT3 is reduced in 87% of breast cancers and this effect is essential for the Warburg effect. Our work shows that increased expression of SOD1 and its import into the IMS is essential to counterbalance the decrease in SIRT3 so that the total levels of O2 in cancer cells remain moderate. Since we found that the increase in SOD1 is independent of oncogene, increased expression of SOD1 maybe a universal housekeeping function of cancer cells to support their metabolic reprogramming. We show that SOD1 levels are regulated by the mitochondria ubiquitin ligase Mulan. Further, we found that accumulation of ROS in the IMS leads to the elimination of Mulan and the stabilization of SOD1. These findings suggest that Mulan acts as a gatekeeper to limit the entry of SOD1 into the IMS. To further test the essential housekeeping function of SOD1 in cancer and to dissect this entirely new mode of regulation of SOD1 by Mulan, we propose the following specific aims:
Specific aim 1 : In vivo validation of SOD1 as a target for therapy.
Specific aim 2 : Testing the regulation of SOD1 by Mulan.
Specific aim 3 : Regulation of Mulan by oxidative stress.
While moderate oxidative stress promotes proliferation, elevated oxidative stress causes cell death. Therefore, cancer cells must maintain their oxidative stress at moderate levels. This application describes a novel SOD1- dependent pathway to limit oxidative stress in cells where the expression of the anti-oxidant SIRT3 is reduced.
| Germain, Doris (2017) Toward the identification and the targeting of key players of the mitochondrial unfolded protein response (UPRmt) in cancer. J Bioenerg Biomembr : |
| Kenny, T C; Hart, P; Ragazzi, M et al. (2017) Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis. Oncogene 36:4393-4404 |
| Kenny, Timothy C; Manfredi, Giovanni; Germain, Doris (2017) The Mitochondrial Unfolded Protein Response as a Non-Oncogene Addiction to Support Adaptation to Stress during Transformation in Cancer and Beyond. Front Oncol 7:159 |
| He, Chenxia; Hart, Peter C; Germain, Doris et al. (2016) SOD2 and the Mitochondrial UPR: Partners Regulating Cellular Phenotypic Transitions. Trends Biochem Sci 41:568-577 |
