Molecular characterization of the hypoxia-induced mitochondrial activity regulator ndufa4l2

Résumé

Biological systems actively control the formation of reactive oxygen species (ROS) in numerous physiopathological scenarios such as those associated with oxygen fluctuations including hypoxia. Along this line, NDUFA4L2 is a target gene of hypoxia-inducible factors (HIF-1 and HIF2α), which prevent excessive generation of ROS via the inhibition of mitochondrial complex I. NDUFA4L2 has gained more interest due to its high expression in numerous tumoral settings and its correlation with a poor disease prognosis. However, these studies are still limited and the in vivo role of NDUFA4L2 as well as its molecular properties to control mitochondrial function remains elusive. Here we have characterized the mitochondrial localization of NDUFAL2 using BN-PAGE analysis revealing an atypical distribution in mitochondrial complexes. Moreover, at the biochemical level, we have identified key features of NDUFA4L2 that could be potentially relevant in the cellular response to oxidative stress. Molecular properties of NDUFA4L2 have been studied not only in in vitro cellular models but also in an Ndufa4l2-deficient mouse model we have generated. Collectively, this dissertation provides a further insight in the molecular biology of Ndufa4l2 that is positioned in the mitochondrial response to oxygen and ROS fluctuations.