Antonina N. Shvetsova, Daniela Mennerich, Juha M. Kerätär, J. Kalervo Hiltunen, Thomas Kietzmann, Non-electron transfer chain mitochondrial defects differently regulate HIF-1α degradation and transcription, Redox Biology, Volume 12, August 2017, Pages 1052-1061, ISSN 2213-2317, https://doi.org/10.1016/j.redox.2017.05.003.
Non-electron transfer chain mitochondrial defects differently regulate HIF-1α degradation and transcription
|Author:||Shvetsova, Antonina N.1,2; Mennerich, Daniela1,2; Kerätär, Juha M.1,2;|
1Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014 Oulu, Finland
2Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland
|Online Access:||PDF Full Text (PDF, 2 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe201706277484
|Publish Date:|| 2017-06-27
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 (20 h) 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.
|Pages:||1052 - 1061|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).