Oxygen is a major regulator of nuclear gene expression. However, although mitochondria consume almost all of the O2 available to the cells, little is known about how O2 tension influences the expression of the mitochondrial genome. We show in O2-sensitive excitable rat PC12 cells that, among the mtDNA-encoded genes, hypoxia produced a specific down-regulation of the transcripts encoding mitochondrial complex I NADH dehydrogenase (ND) subunits, particularly ND4 and ND5 mRNAs and a stable mRNA precursor containing the ND5 and cytochrome b genes. This unprecedented effect of hypoxia was fast (developed in <30 min) and fairly reversible and occurred at moderate levels of hypoxia (O2 tensions in the range of 20-70 mm Hg). Hypoxic down-regulation of the mitochondrial complex I genes was paralleled by the reduction of complex I activity and was retarded by iron chelation, suggesting that an iron-dependent post-transcriptional mechanism could regulate mitochondrial mRNA stability. It is known that cell respiration is under tight control by the amount of proteins in mitochondrial complexes of the electron transport chain. Therefore, regulation of the expression of the mitochondrial (mtDNA)-encoded complex I subunits could be part of an adaptive mechanism to adjust respiration rate to the availability of O2 and to induce fast adaptive changes in hypoxic cells.