Hypoxia has been shown to decrease ATP-consuming processes such as Na/K-ATPase and protein synthesis. We have shown previously that this was associated with decreased mitochondrial O2-consumption and decreased activity of mETC complexes 1, 2 and 3 (Heerlein et al. AJRCMB 32:44 (2005). Here we tested, whether decreased respiratory activity is associated with altered expression of mETC enzymes encoded on the nuclear and mitochondrial genome, as well as expression of potential regulators. Confluent human A549 cells were exposed to hypoxia (5% and 1.5% O2) for 4h, 24h and 48h. mRNA expression was measured by qRT-PCR using 28S rRNA for normalization. Severe hypoxia for 24h and 48h caused a decreased mRNA expression of the nuclear-encoded NDUFS8 of complex 1 and SDHB of complex 2. Also the messages for the mitochondrial encoded cytochrome B, cytochrome oxidase-1, and ATPase-6 were decreased. At 5% O2, there was a decrease in mRNA expression only after 24h but recovery thereafter. These changes were paralleled by a transient decrease (5% O2, 24h) and pronounced decrease (1.5% O2, 24h, 48h) of mRNA and protein of the key activator of mitochondrial transcription, TFAM. 1.5% O2 had no effect on the mRNA expression of AMP-kinase, PPAR, NRF-1 and NRF-2. There expression appeared up-regulated after 48h at 5% O2. Our results indicate that decreased mitochondrial respiration in severe hypoxia is associated with a decreased expression of key enzymes of the mETC, which is probably caused by decreased TFAM consistent with mitochondrial autophagy.