Professor (also with Internal Medicine); Ph.D., Yeshiva University (Albert Einstein College of Medicine), 1971. Molecular genetics and evolution of the electron transport chain; cytochrome c oxidase; mitochondria and mitochondrial disease.
Research Interests
My lab studies the molecular genetics and evolution of mitochondrial genes. The goal is to understand their detailed function and how their expression and function is regulated. Some proteins of the electron transport chain are encoded by mitochondrial DNA and some by nuclear DNA. We have largely focused on the nuclear-encoded subunits, particularly those of cytochrome c oxidase (CcO), the terminal enzyme complex of the respiratory chain. The known functions of CcO are carried out by the three subunits specified by mitochondrial DNA; the role of the nuclear subunits is only beginning to emerge and includes regulation.
In our focus on the function, regulation, and molecular evolution of the nuclear subunits, we have needed to first establish the players. To that end, we recently discovered three new CcO isoforms, a lung and trachea-specific isoform of subunit IV, a testes-specific isoform of subunit VIb, and a third isoform of subunit VIII. We are currently examining the lung-specific isoform in particular detail, both by studying its transcriptional regulation, especially by hypoxia, to understand its signaling circuitry and interaction with other cellular components, and by examining a recently created mouse null mutant.
Another approach to function we are using is molecular evolution; we have developed the picture that cytochrome c and subunits of complex III and CcO that interact with it have undergone a period of accelerated evolution suggestive of positive selection at similar times in an ancestor of modern primates. We have speculated that this accelerated evolution was ultimately driven by the energetic needs of an enlarged neocortex. A portion of this acceleration has had the effect of remodeling the docking site of cytochrome c on cytochrome oxidase so as to change the binding interaction from a predominantly electrostatic one to a predominantly hydrophobic one. We are now seeking to characterize biochemically any modifications in electron transport that resulted. Finally, we are interested in the relation between rapidly evolving genes and human disease.
Selected Publications
T.R. Schmidt, W. Wu, J.R. Doan, M. Goodman and L.I. Grossman (2003). Retention of a duplicate gene through changes of the subcellular localization signal: a cytochrome c oxidase subunit VIIa-related protein localizes to the Golgi apparatus. J. Mol. Evol. 57, 222-228.
A. Goldberg, T.R. Schmidt, M. Hüttemann, D. Wildman, M. Weiss, M. Goodman and L.I. Grossman (2003). Adaptive evolution of cytochrome c oxidase subunit viii in anthropoid primates. Proc. Natl. Acad. Sci. USA 100, 5873-5878.
M. Hüttemann, S. Jaradat and L.I. Grossman (2003). Cytochrome c oxidase of mammals contains a testes-specific isoform of subunit VIb-the counterpart to testes-specific cytochrome c? Molec. Repro. Dev. 66, 8-16.
M. Hüttemann, T.R. Schmidt and L.I. Grossman (2003). A third isoform of cytochrome c oxidase subunit VIII is present in mammals. Gene 312, 95-102.
D.E. Wildman, M. Uddin, G. Liu, L.I. Grossman and M. Goodman (2003). The 99.4% nonsynonymous and 98.4% synonymous sequence identity between chimpanzees and humans: implications for Darwinian selection and for enlarging the genus Homo. Proc. Natl. Acad. Sci. USA 100, 7181-7188.
M. Uddin, D.E. Wildman, G. Liu, W. Xu, R.M. Johnson, P.R. Hof, G. Kapatos, L.I. Grossman and M. Goodman (2004). Sister grouping of chimpanzees and humans as revealed by genome-wide phylogenetic analysis of brain gene expression profiles. Proc. Natl. Acad. Sci. USA 101, 2957-2962.
J.W. Doan, T.R. Schmidt, D.E. Wildman, M. Uddin, A. Goldberg, M. Hüttemann, M. Goodman, M.L. Weiss and L.I. Grossman (2004). Coevolution of a multiprotein complex: cytochrome c oxidase subunits show accelerated rates of nonsynonymous substitution in anthropoid primates. Mol. Phylogenet Evol. 33, 944-950.
L.I. Grossman, D.E. Wildman, T.R. Schmidt and M. Goodman (2004). Accelerated evolution of the electron transport chain in anthropoid primates. Trends Genet. 20 , 579-585.
J.W. Doan, T.R. Schmidt, D.E. Wildman, M. Goodman, M.L. Weiss and L.I. Grossman (2005). Rapid nonsynonymous evolution of the iron sulfur protein in anthropoid primates. J. Bioenerg. Biomembr. 37, 35-41.
I. Lee, A.R. Salomon, S. Ficarro, I. Mathes, F. Lottspeich, L.I. Grossman, and M. Hüttemann (2005). cAMP-dependent tyrosine phosphorylation of subunit I inhibits cytochrome c oxidase activity. J. Biol. Chem. 280, 6094-6100.
M. Goodman, L.I. Grossman and D.E. Wildman (2005). Moving primate genomics beyond the chimpanzee genome. Trends Genet. 21, 511-517.
D.E. Wildman, C. Chen, O. Erez, L.I. Grossman, M. Goodman and R. Romero (2006). Evolution of the mammalian placenta revealed by phylogenetic analysis. Proc. Natl. Acad. Sci. USA 103, 3203-3208.
I. Lee, A.R. Salomon, K. Yu, J.W. Doan, L.I. Grossman and M. Hüttemann (2006). New prospects for an old enzyme: mammalian cytochrome c is tyrosine phosphorylated in vivo. Biochemistry 45, 9121-9128.
C.C. Sherwood, C.D. Stimpson, M.A. Raghanti, D.E. Wildman, M. Uddin, L.I. Grossman, M. Goodman, J.C. Redmond, C.J. Bonar, JM. Erwin and P.R. Hof (2006). Evolution of Increased Glia-Neuron Ratios in the Human Frontal Cortex. Proc. Natl. Acad. Sci. USA 103, 13606-13.
M. Uddin, J.C. Opazo, D.E. Wildman, C.C. Sherwood, P. Hof, M. Goodman and L.I. Grossman (2007). Molecular evolution of the cytochrome c oxidase subunit 5A gene in primates. BMC Evol. Biol., in press.
C. Chen, J.C. Opazo, O. Erez, M. Uddin, J. Santolaya-Forgas, M. Goodman, L.I. Grossman, R. Romero and D.E. Wildman (2007). Mammalian progesterone receptors show evidence of adaptive evolution associated with N-terminus transactivation and transrepression function. Mol. Phylogenet Evol., in press.
M. Hüttemann, I. Lee, J. Liu and L.I. Grossman (2007). Transcription of cytochrome c oxidase subunit IV-2 is controlled by a novel conserved oxygen responsive element. FEBS J 274, 5737-5748.
G. Liu, M. Uddin, M. Goodman, L.I. Grossman, R. Romero, D.E. Wildman (2007). OCPAT: an online codon-preserved alignment tool for evolutionary genomic analysis of protein coding sequences. Source Code for Biology and Medicine 2:5.
D.E. Wildman, M. Uddin, J.C. Opazo, G. Liu, V. Lefort, O. Gascuel, L.I. Grossman, R. Romero, and M. Goodman (2007). Genomics, biogeography, and the diversification of placental mammals. Proc. Natl. Acad. Sci. USA 104, 14395-14400.
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