Research Interests

We study cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain. COX contains 13 subunits, 3 of which are mitochondrial encoded, the remainder being nuclear encoded. The functional enzyme in mammals is a dimer.

Respiratory chain complexes I (NADH dehydrogenase), III (bc1 complex), and IV (COX) pump protons across the inner mitochondrial membrane and generate the mitochondrial membrane potential. The pumped protons are used by ATP synthase to generate ATP from ADP and Pi. COX catalyzes the transfer of electrons from reduced cytochrome c to molecular oxygen and consumes protons from the mitochondrial matrix side in the water formation reaction, which also contributes to the generation of the membrane potential. 

Mammalian COX has skeletal muscle (H-type) and non muscle (L-type) isoforms of subunits VIa, VIIa, and VIII, which have been known for more than 2 decades. We have recently doubled this number and discovered. 1) a lung-specific isoform of subunit IV, which is highly expressed in the smooth muscle of the lung; 2) a testes-specific isoform of subunit VIb, which is the exlusive isoform in rodent testes but co-expressed with the "somatic" isoform in human and bull; and 3) a third isoform of subunit VIII, which localizes to the mitochondria although the tissue where it is primarily expressed remains elusive at this point. One of our goals is to understand the regulation of mammalian COX via isoform expression. We believe that tissue-specific energy needs are at least in part reflected by isoform expression. Consequently, analyzing COX isozymes will help us to understand the function(s) of individual subunits and their isoforms. We also address the question of possible disease relatedness, e.g., involvement of the lung isoform in lung diseases and the testes isoform in human infertility.

In an interest shared with Larry Grossman, we aim to understand COX subunit gene regulation. Of special interest to us are COX isoforms, which are in part developmentally regulated.

Selected Publications

1. Hüttemann, M., Arnold, S., Lee, I., Mühlenbein, N., Linder D., Lottspeich F., Kadenbach, B. (2000). Turkey cytochrome c oxidase contains subunit VIa of the liver type associated with low efficiency of energy transduction. Eur J Biochem 267, 2098-104.
2. Hüttemann, M., Mühlenbein, N., Schmidt, T.R., Grossman, L.I., Kadenbach, B. (2000). Isolation and analysis of the gene for subunit VIlaL of cytochrome c oxidase. Biochim Biophys Acta 1492, 252-258.
3. Hüttemann, M. (2000). New isoforms of cytochrome c oxidase subunit IV in tuna fish. Biochim Biophys Acta 1492, 252-258.
4. Kadenbach B., Hüttemann M., Arnold S., Lee I., Bender E. (2000). Mitochondrial energy metabolism is regulated via nuclear-coded subunits of cytochrome c oxidase. Free Radic Biol Med. 29. 211-221.
5. Hüttemann, M., Kadenbach, B. and Grossman, L.I. (2001). Mammalian subunit IV isoforms of cytochrome c oxidase. Gene 267, 111-123.
6. Ludwig, B., Bender E., Arnold S., Hüttemann M., Lee I. and Kadenbach B. (2001). Cytochrome c oxidase and the regulation of oxidative phosphorylation. Chembiochem. 2, 392-403.
7. Hüttemann, M. (2002). Partial heat denaturation step during reverse transcription and PCR screening yields full-length 5'-cDNAs. Biotechniques 32, 730-736.
8. Goldberg, A., Wildman, D.E., Schmidt, T.R., Hüttemann, M., Goodman, M., Weiss, M.L., Grossman, L.I. (2003) Adaptive evolution of cytochrome c oxidase subunit VIII in anthropoid primates. Proc Natl Acad Sci, 100, 5873-8..
9. Hüttemann, M., Schmidt, T.R., Grossman, L.I. (2003) A third isoform of cytochrome c oxidase subunit VIII is present in mammals. Gene, in press.