| First Author | Shvetsova AN | Year | 2017 |
| Journal | Redox Biol | Volume | 12 |
| Pages | 1052-1061 | PubMed ID | 28531964 |
| Mgi Jnum | J:319246 | Mgi Id | MGI:6863318 |
| Doi | 10.1016/j.redox.2017.05.003 | Citation | Shvetsova AN, et al. (2017) Non-electron transfer chain mitochondrial defects differently regulate HIF-1alpha degradation and transcription. Redox Biol 12:1052-1061 |
| abstractText | Mitochondria are the main consumers of molecular O2 in a cell as well as an abundant source of reactive oxygen species (ROS). Both, molecular oxygen and ROS are powerful regulators of the hypoxia-inducible factor-1alpha-subunit (HIF-alpha). While a number of mechanisms in the oxygen-dependent HIF-alpha regulation are quite well known, the view with respect to mitochondria is less clear. Several approaches using pharmacological or genetic tools targeting the mitochondrial electron transport chain (ETC) indicated that ROS, mainly formed at the Rieske cluster of complex III of the ETC, are drivers of HIF-1alpha activation. However, studies investigating non-ETC located mitochondrial defects and their effects on HIF-1alpha regulation are scarce, if at all existing. Thus, in the present study we examined three cell lines with non-ETC mitochondrial defects and focused on HIF-1alpha degradation and transcription, target gene expression, as well as ROS levels. We found that cells lacking the key enzyme 2-enoyl thioester reductase/mitochondrial enoyl-CoA reductase (MECR), and cells lacking manganese superoxide dismutase (MnSOD) showed a reduced induction of HIF-1alpha under long-term (20h) hypoxia. By contrast, cells lacking the mitochondrial DNA depletion syndrome channel protein Mpv17 displayed enhanced levels of HIF-1alpha already under normoxic conditions. Further, we show that ROS do not exert a uniform pattern when mediating their effects on HIF-1alpha, although all mitochondrial defects in the used cell types increased ROS formation. Moreover, all defects caused a different HIF-1alpha regulation via promoting HIF-1alpha degradation as well as via changes in HIF-1alpha transcription. Thereby, MECR- and MnSOD-deficient cells showed a reduction in HIF-1alpha mRNA levels whereas the Mpv17 lacking cells displayed enhanced HIF-1alpha mRNA levels under normoxia and hypoxia. Altogether, our study shows for the first time that mitochondrial defects which are not related to the ETC and Krebs cycle contribute differently to HIF-1alpha regulation by affecting HIF-1alpha degradation and HIF-1alpha transcription where ROS play not a major role. |
