Faculty and Research Interests
Michael Henry, PhD
Science Center 320
Alterations in mitochondrial gene expression can compromise cellular energy production and generate reactive oxygen species that promote degenerative disease, aging, and cancer. The formation of the respiratory chain is under control of two separate genetic systems, the nuclear genome and the mitochondrial genome. The mitochondrial genome encodes several subunits of the respiratory chain, and their coordinated expression is essential for proper function. Their regulation is distinct from nuclear and bacterial genes in that they are predominantly controlled by translational, rather than transcriptional, activation. A clearer understanding of how this system is regulated is necessary to better understand mitochondrial disease.
Our research is aimed at understanding how the translation of mitochondrial mRNAs within this organelle are controlled by nuclear genes, and how mitochondrially coded proteins are assembled with nuclear-encoded proteins into the respiratory chain complexes (Figures 1 and 2). The budding yeast Saccharomyces cerevisiae is especially well suited to study these interactions, as yeast can rely exclusively on glucose fermentation for its energy requirement, and therefore survive without oxidative phosphorylation. This means that it is possible to analyze the consequences of severe defects in respiratory complexes, which in other organisms would be lethal. Furthermore, both nuclear and mitochondrial genomes can be isolated and manipulated. Hence, it is possible to introduce specific mutations into both nuclear- and mtDNA-encoded subunits of the respiratory complexes.
Figure 1. Model of coupled mitochondrial gene expression in yeast. Mitochondrially encoded mRNAs are first channeled from RNA polymerase to membrane bound ribosomes by Sls1, Mtf2, Rmd9 and mRNA-specific translational activators (TA). Respiratory proteins that emerge from the membrane-bound ribosomes are cotranslationally transferred to Oxa1 for membrane insertion. The figure is not intended to suggest that mRNAs are translated while still emerging from RNA polymerase.
Figure 2. Schematic drawing of the respiratory chain and yeast mitochondrial DNA. Top: respiratory chain complexes. Mitochondrially encoded subunits, embedded in the midst of nuclear-encoded subunits, are shown in different colors: complex III subunit = green; complex IV subunits = red; complex V subunits = yellow (adapted from Zeviani and Di Donato, Brain, 2004). Bottom: mtDNA
- Henry, M.F., Mandel D., Routson, V. and Henry, P.A. 2003. The Yeast hnRNP-like protein Hrp1/Nab4 accumulates in the cytoplasm following hyperosmotic stress: a novel Fps1-dependent response. Mol Biol. Cell. 14:3929-3941
- Xu, C., Henry, P.A., Setya S. and Henry M.F. 2003. In vivo analysis of nucleolar proteins modified by the yeast arginine methyltransferase Hmt1/Rmt1p. RNA. 6:746-759
- González, C.L., Ruiz-Echevarría, M.J., Vasudevan, S. W. , Henry, M.F.,and S.W. Peltz. 2000. Mutations in HRP1 Suggest That A Nucleocytoplasmic Cross-Talk Is Involved In Nonsense-Mediated mRNA Decay. Mol Cell. 5:489-99
- Gratzer, S., Beilharz, T., Beddoe, T., Henry, M.F., and T. Lithgow. 2000. The mitochondrial protein targeting suppressor (mts1) mutation maps to the mRNA-binding domain of Npl3p and effects translation on cytoplasmic ribosomes. Mol Microbiol. 35: 1277-85
- Klein, S., Carroll, J.A., Chen, Y., Henry, M.F., Ortonowski, I., Gravotta, D., Pinucci, G., Beavis, R.C., Burgess, W.H. and Rifken, D.B. 2000. Biochemical Analysis of the Methylation of high Molecular Weight Fibroblast Growth Factor-2. J Biol Chem. 275:3150-7
- Scott*, H.S., Antonarakis, S.E., Lalioti, M.D., Rossier,C., Silver, P.A., and M.F. Henry*. 1998. Identification and characterization of two putative human arginine methyltransferases (HRMT1L1 and HRMT1L2). Genomics 48: 330-340
- Shen, E.C., Henry, M.F., Weiss, V.H., Valentini, S.R., Silver, P.A., and Lee, M.S. (1998) Arginine methylation facilitates the nuclear export of hnRNP proteins. Genes Dev. 12: 679-691
- Kessler*, M., Henry*, M.F., Shen E., Gross, S., Silver, P.A., and C. Moore. 1998. HRP1 is a specific RNA binding protein that shuttles between the nucleus and cytoplasm and is required for 3' end formation in yeast. Genes Dev. 11: 2545-2556
- Corbett, A.H., Ferrigno, P., Henry, M.F., Kahana, J., Koepp, D.M., Lee, M.S., Nguyen, L., Schlenstedt, G., Seedorf, M., Shen, E.C., Taura, T., Wong, D.H., and P.A. Silver. 1996. Genetic Analysis of Macromolecular Transport across the Nuclear Envelope. In: Proceedings of the Nobel Symposium on the Nucleus. Exp. Cell Res. 229: 212-216
- Henry, M.F., and P.A. Silver. 1996. A Novel Methyltransferase (HMT1) Modifies Poly(A)+ RNA-Binding Proteins. Mol. Cell. Biol. 16: 3668-3678
- Lee, M.S., M.F. Henry, and P.A. Silver. 1996. A Protein That Shuttles Between the Nucleus and the Cytoplasm is an Important Mediator of RNA Export. Genes Dev. 10: 1233-1246.
- Henry, M.F., C.Z. Borland, M. Bossie, and P.A. Silver. 1996. Potential RNA Binding Proteins in Saccharomyces cerevisiae Identified as Suppressors of Temperature-Sensitive Mutations in NPL3. Genetics 142: 103-115
- Henry M.F., and J.E. Cronan, Jr. 1992. A New Mechanism of Transcriptional Regulation: Release of an Activator Triggered by Small Molecule Binding. Cell 70: 671-679.
- Henry, M.F., and J.E. Cronan, Jr. 1991. Escherichia coli Transcription Factor That Both Activates Fatty Acid Synthesis and Represses Fatty Acid Degradation. J. Mol. Biol. 222:843-849.
- Henry, M.F., and J.E. Cronan, Jr. 1991. A Direct and General Selection for Lysogens of Escherichia coli by Phage Lambda Recombinant Clones. J. Bacteriol. 173:3724-3731.
- Henry, M.F., and J.E. Cronan, Jr. 1989. A Facile and Reversible Method to Decrease the Copy Number of ColE1-Related Cloning Vectors Commonly Used in Escherichia coli. J. Bacteriol. 122:5254-5261.