Mitochondrial genetics, regulation, and disease

A major overall goal of our lab is to understand how the cell stays in touch with its energy supply and adjusts its activities to maintain adequate and healthy energetics. We study the function and regulation of mitochondrial genes, focusing on the rate limiting electron transport chain complex, cytochrome c oxidase (COX) and its regulators. COX is composed of 13 subunits: the 3 largest are coded by mitochondrial DNA, the other 10 by nuclear DNA. A fourteenth subunit is associated with both COX and Complex I. 

Cytochrome c oxidase subunit 4
We first isolated the genes for COX subunit 4 and, more recently, a second version (isoform), COX4i2. We find that COX4i2 has a restricted tissue expression and that it makes the COX holoenzyme work more rapidly. Surprisingly, it plays a crucial role in hypoxia sensing both in the lung and in the carotid body and we have been studying the mechanism by which it does so. 

Selected publications:

Oxygen-dependent expression of cytochrome c oxidase subunit 4-2 gene expression is mediated by transcription factors RBPJ, CXXC5, and CHCHD2
Aras S, Pak O, Sommer N, Finley RL Jr., Hüttemann M, Weissmann N, Grossman LI  
Nucleic Acids Res 1-12 (2013).

Mice deleted for heart-type cytochrome c oxidase subunit 7a1 develop dilated cardiomyopathy
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 
Mitochondrion 12: 294-304 (2012).

Cytochrome c oxidase subunit 4 isoform 2 knockout mice show reduced enzyme activity, airway hyporeactivity, and lung pathology
Hüttemann M, Lee I, Gao X, Pecina P, Pecinova A, Liu J, Aras S, Sinkler C, Sommer N,  Sanderson TH, Tost M, Neff F, Aguilar-Pimentel JA, Becker L, Naton B, Rathkolb B, Rozman J, Favor J, Hans W, Prehn C, Puk O, Schrewe A, Sun M, Hüfler H, Adamski J, Bekeredjian R, Graw J, Adler T, Busch DH, Klingenspor M, Klopstock T, Ollert M, Wolf E, Fuchs H, Gailus-Durner V, Hrab de Angelis M, Weissmann N, Doan JW,. Bassett DJP, and Grossman LI 
FASEB J 26, 3916-3930 (2012).

Phosphorylation of mammalian cytochrome c and cytochrome c oxidase in the regulation of cell destiny: respiration, apoptosis, and human disease
Hüttemann M, Lee I, Grossman LI, Doan JW, Sanderson TH 
Adv Exp Med Biol 748: 237-64 (2012).

Deletion of heart-type cytochrome c oxidase subunit 7A1 impairs skeletal muscle angiogenesis and oxidative phosphorylation 
Lee I, Hüttemann M, Liu J, Grossman LI, Malek MH 
J Physiol 590, 5231-5243 (2012).

We also study mitochondrial evolution, an area in which we have two main interests. We are interested in the evolution of individual subunit genes and its function. We have a particular interest in cytochrome c oxidase (COX). 

Selected publications on mitochondrial evolution and genomics

Developmental changes in the transcriptome of human cerebral cortex tissue: Long noncoding RNA transcripts
Lipovich L, Tarca A, Cai J, Jia H, Chugani HT, Sterner K, Grossman LI, Uddin M, Hof PR, Sherwood CC, Kuzawa CW, Goodman M, Wildman DE 
Cerebral Cortex, in press.

MITOGROUP: Continent-specific clusters of mitochondrial OXPHOS complexes based on nuclear non-synonymous polymorphisms
Pierron D, Letellier T and Grossman LI 
Mitochondrion 12: 237-24 (2012).

Silencing, positive selection and parallel evolution: Busy history of primate cytochromes c
Pierron D, Opazo JC, Heiske M, Papper Z,  Uddin M, Chand G, Wildman DE, Romero R, Goodman M, Grossman LI
PLOS One, 6(10): e26269 (2011).

Phylogenomic Analyses Reveal Convergent Patterns of Adaptive Evolution in Elephant and Human Ancestries
Goodman M, Sterner KN, Islam M, Uddin M, Sherwood CC, Hof PR, Hou ZC, Lipovich L, Jia H, Grossman LI and Wildman DE
Proc Natl Acad Sci USA 106: 20824-29 (2009).

Evolution of Increased Glia-Neuron Ratios in the Human Frontal Cortex
Sherwood CC, Stimpson CD, Raghanti MA, Wildman DE, Uddin M, Grossman LI, Goodman M,  Redmond JC, Bonar CJ, Erwin JM and Hof PR
Proc Natl Acad Sci USA, 103, 13606-13 (2006).

Rapid electrostatic evolution at the docking site for cytochrome c on cytochrome c oxidase in anthropoid primates
Schmidt TR, Wildman DE, Uddin M, Opazo J, Goodman M and Grossman LI
Proc Natl Acad Sci USA 102, 6379-6384 (2005).