|Lawrence I. Grossman, Ph.D.
Henry L. Brasza Director
3303 Scott Hall
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.
My lab studies nuclear encoded mitochondrial genes. We focus on their regulation and function in energy metabolism and the pathologies associated with their dysfunction. 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.
A recent interest has been a lung and trachea-specific isoform of subunit IV that we discovered, CcO4-2. 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.
A specific area of emphasis is preterm birth and its relation to metabolic dysfunction in energy metabolism.
We are also interested in their molecular evolution; we have developed the picture that cytochrome c and subunits of complex III and of CcO that interact with it have undergone a period of accelerated evolution suggestive of positive selection during primate ancestry. 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 CcO so as to change the binding interaction from a predominantly electrostatic one to a predominantly hydrophobic one. We are now seeking to characterize biochemically resulting modifications in electron transport. More generally, we are interested in the genetic changes that have made us uniquely human, and in the relation between rapidly evolving genes and human disease.
Hüttemann M, Helling S, Sanderson TH, Sinkler C, Samavati L, Mahapatra G, Varughese A, Lu G, Liu J, Ramzan R, Vogt S, Grossman LI, Doan JW, Marcus K, Lee I (2012). Invited review: Regulation of mitochondrial respiration and apoptosis through cell signaling: Cytochrome c oxidase and cytochrome c in ischemia/reperfusion injury and inflammation. Biochim Biophys Acta 1817:59-609.
Pierron D, Wildman DE, Hüttemann M, Markondapatnaikuni GC, Aras S and Grossman LI (2012). Invited review: Cytochrome c oxidase: Evolution of control via nuclear subunit addition. Biochim Biophys Acta 1817:590-7.
Hüttemann M, Klewer S, Lee I, Pecinova A, Pecina P, Liu J, Lee M, Doan JW, Larson D, Slack E, Maghsoodi B, Erickson RP, Grossman LI (2011). Mice deleted for heart-type cytochrome c oxidase subunit 7a1 develop dilated cardiomyopathy. Mitochondrion [Epub ahead of print].
Pierron D, Opazo JC, Heiske M, Papper Z, Uddin M, Chand G, Wildman DE, Romero R, Goodman M, Grossman LI (2011). Silencing, positive selection and parallel evolution: Busy history of primate cytochromes c. PLOS One, 6(10): e26269.
Pierron D, Letellier T and Grossman LI (2011). MITOGROUP: Continent-specific clusters of mitochondrial OXPHOS complexes based on nuclear non-synonymous polymorphisms. Mitochondrion [Epub ahead of print].
Goodman M, Sterner KN, Islam M, Uddin M, Sherwood CC, Hof PR, Hou ZC, Lipovich L, Jia H, Grossman LI and Wildman DE (2009). Phylogenomic Analyses Reveal Convergent Patterns of Adaptive Evolution in Elephant and Human Ancestries. Proc Natl Acad Sci USA 106: 20824-29.
Than NG, Romero R, Goodman M, Weckle A, Xing J, Dong Z, Xu Y, Tarquini F, Szilagyi A, Gal P, Hou Z, Tarca AL, Kim CJ, Kim JS, Haidarian S, Uddin M, Bohn H, Benirschke K, Santolaya-Forgas J, Grossman LI, Erez O, Hassan SS, Zavodszky P, Papp Z and Wildman DE (2009). A primate subfamily of galectins expressed at the maternal-fetal interface that promote immune cell death. Proc Natl Acad Sci USA 106: 9731-9736.
Than NG, Romero R, Erez O, Weckle A, Hotra J, Abbas A, Han YM, Kim S-S, Kusanovic JP, Gotsch F, Hou Z, Santolaya-Forgas J, Benirschke K, Papp Z, Grossman LI, Goodman M and Wildman DE (2008). Emergence of hormonal and redox regulation of galectin-1 in placental mammals – implication in maternal-fetal immune tolerance. Proc Natl Acad Sci USA 105: 15819-24.
Uddin M, Goodman M, Erez O, Romero R, Liu G, Islam M, Opazo JC, Sherwood CC, Grossman LI and Wildman DE (2008). Distinct genomic signatures of adaptation in pre-and post-natal environments during human evolution. Proc Natl Acad Sci USA 105, 3215-3220.
Chen C, Opazo JC, Erez O, Uddin M, Santolaya-Forgas J, Goodman M, Grossman LI, Romero R and Wildman DE (2008). Mammalian progesterone receptors show evidence of adaptive evolution associated with N-terminus transactivation and transrepression function. Mol Phylogenet Evol 47, 637-649.
Uddin M, Opazo JC, Wildman DE, Sherwood CC, Hof P, Goodman M and Grossman LI (2008). Molecular evolution of the cytochrome c oxidase subunit 5A gene in primates. BMC Evol Biol 8:8.
Wildman DE, Uddin M, Opazo JC, Liu G, Lefort V, Gascuel O, Grossman LI, Romero R and Goodman M (2007). Genomics, biogeography, and the diversification of placental mammals. Proc Natl Acad Sci USA 104, 14395-14400.
Liu G, Uddin M, Goodman M, Grossman LI, Romero R and Wildman DE (2007). OCPAT: an o nline c odon- p reserved a lignment t ool for evolutionary genomic analysis of protein coding sequences. Source Code for Biology and Medicine 2:5.
Sherwood CC, Stimpson CD, Raghanti MA, Wildman DE, Uddin M, Grossman LI, Goodman M, Redmond JC, Bonar CJ, Erwin JM and Hof PR (2006). Evolution of Increased Glia-Neuron Ratios in the Human Frontal Cortex. Proc Natl Acad Sci USA, 103, 13606-13.
Wildman DE, Chen C, Erez O, Grossman LI, Goodman M and Romero R (2006). Evolution of the mammalian placenta revealed by phylogenetic analysis. Proc Natl Acad Sci USA 103, 3203-3208.
Lee I, Salomon AR, Yu K, Doan JW, Grossman LI and Hüttemann M (2006). New Prospects for an Old Enzyme: Mammalian Cytochrome c is Tyrosine Phosphorylated in vivo. Biochemistry 45, 9121-9128.