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-1α-subunit (HIF-α). While a number of mechanisms in the
oxygen-dependent HIF-α 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-1α activation. However, studies investigating non-ETC located
mitochondrial defects and their effects on HIF-1α 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-1α 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-1α under long-term (20h)
hypoxia. By contrast, cells lacking the
mitochondrial DNA depletion syndrome channel
protein Mpv17 displayed enhanced levels of HIF-1α already under normoxic conditions. Further, we show that ROS do not exert a uniform pattern when mediating their effects on HIF-1α, although all
mitochondrial defects in the used cell types increased ROS formation. Moreover, all defects caused a different HIF-1α regulation via promoting HIF-1α degradation as well as via changes in HIF-1α transcription. Thereby, MECR- and MnSOD-deficient cells showed a reduction in HIF-1α
mRNA levels whereas the Mpv17 lacking cells displayed enhanced HIF-1α
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-1α regulation by affecting HIF-1α degradation and HIF-1α transcription where ROS play not a major role.