Induction of the Mitochondrial NDUFA4L2 Protein by HIF-1α Decreases Oxygen Consumption by Inhibiting Complex I Activity

SummaryThe fine regulation of mitochondrial function has proved to be an essential metabolic adaptation to fluctuations in oxygen availability. During hypoxia, cells activate an anaerobic switch that favors glycolysis and attenuates the mitochondrial activity. This switch involves the hypoxia-inducible transcription factor-1 (HIF-1). We have identified a HIF-1 target gene, the mitochondrial NDUFA4L2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2). Our results, obtained employing NDUFA4L2-silenced cells and NDUFA4L2 knockout murine embryonic fibroblasts, indicate that hypoxia-induced NDUFA4L2 attenuates mitochondrial oxygen consumption involving inhibition of Complex I activity, which limits the intracellular ROS production under low-oxygen conditions. Thus, reducing mitochondrial Complex I activity via NDUFA4L2 appears to be an essential element in the mitochondrial reprogramming induced by HIF-1.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (108 K)Download as PowerPoint slideHighlights▸ NDUFA4L2 is a HIF-1α target gene that localizes to the mitochondria ▸ NDUFA4L2 downregulates oxygen consumption and Complex I activity in hypoxia ▸ NDUFA4L2 is involved in hypoxic adaptation by decreasing mitochondrial ROS production ▸ NDUFA4L2 homozygous knockout mice die perinatally