Margaret Wong-Riley, PhD
Medical College of Wisconsin
Department of Cell Biology, Neurobiology & Anatomy
8701 Watertown Plank Road
Milwaukee, WI 53226-0509
(414) 955-6517 (fax)
Margaret Wong-Riley, PhD
Editor-in-Chief, Eye and Brain
PhD, Stanford University, Stanford, CA, 1970
Postdoctoral, Postdoctoral, University of Wisconsin, Madison, 1970-71
Lab of Neurophysiology, National Institutes of Health, 1972-73
Program in Cell and Developmental Biology
Program in Neuroscience
Coupling of neuronal activity and energy metabolism at the cellular and molecular levels. Cytochrome c oxidase as a metabolic marker for neuronal activity. Transcriptional regulation of cytochrome c oxidase and neurotransmitter receptors. Metabolic and neurochemical plasticity in the adult visual system. Critical period of neurochemical and metabolic development in brain stem respiratory neurons. Photobiomodulation of neurons functionally inactivated by toxins.
Our laboratory is interested in the ability of mature neurons to undergo plastic changes in response to altered functional demands. The central hypothesis is that neuronal activity and energy metabolism are tightly coupled; thus, the level of an energy-generating enzyme such as cytochrome c oxidase should correlate positively with the level of neuronal activity.
Since cytochrome c oxidase is a highly sensitive marker of neuronal activity, we are investigating its mechanism of regulation in the brain. We have found that the level of activity of this enzyme is regulated at its protein level, which, in turn, is regulated at its message and mitochondrial DNA levels. Moreover, the molecular activity, amount, and mRNA of this protein in the nervous system are under the tight control of neuronal activity.
Cytochrome c oxidase is one of only four proteins in mammalian cells that are bigenomically encoded. Its largest three subunits are encoded in the mitochondrial genome and form the catalytic core of the enzyme, whereas the other ten subunits are encoded in the nuclear genome. Thus, it serves as an excellent model for studying bigenomic regulation of proteins. Neurons also pose a unique challenge in that mitochondrial genome in distal dendrites and axons can be far removed from the nucleus. The key question is, how do the two genomes coordinate their regulation to form a functional holoenzyme with one-to-one stoichiometry of 13 subunits? Does one genome play a more important role than the other? Are there transcription factors that can serve as bigenomic coordinators?
Two candidates have been found: nuclear respiratory factors 1 and 2 (NRF-1 and NRF-2). These transcription factors directly activate all 10 nuclear-encoded cytochrome oxidase subunit genes as well as indirectly regulate the 3 mitochondrial-encoded subunit genes by activating other transcription factors, mitochondrial transcription factors A and B (Tfam, Tfb1m, and Tfb2m), which play important roles in regulating the transcription and replication of mitochondrial DNA. Recently, we found that all 13 genomic loci interact in the same dynamic transcription factory in the nucleus. An important transcriptional co-activator of NRF-1 and NRF-2, known as PGC-1a (peroxisome proliferator-activated receptor gamma coactivator-1a), is also under study.
If neuronal activity is tightly coupled to energy metabolism at the cellular level, is it possible that the two processes are co-regulated at the molecular level? We are exploring transcription factor/s that may play such a dual role. Thus far, we found that NRF-1 transcriptionally co-regulates cytochrome c oxidase and vital glutamatergic neurochemicals, such as Grin1 and Grin2b of NMDA receptors, Gria2 of AMPA receptors, and Nos1 (neuronal nitric oxide synthase). Moreover, NRF-1 regulates the expression of Kif17, a known motor for its cargo, NR2B. Such transcriptional coupling ensures that energy supply keeps pace with energy demand of glutamatergic synaptic transmission with high efficiency and precision.
Wong-Riley, Eye and Brain, 2010
Another research area is probing for the metabolic, neurochemical, ventilatory, and physiological bases of a critical period in respiratory development. The impetus for this research is that SIDS (Sudden Infant Death Syndrome) has its peak incidence not at birth, but between the 2nd and 4th postnatal months, suggesting that there is a critical period of postnatal development when a seemingly normal infant may succumb to SIDS. In a rat model, we found a narrow window toward the end of the 2nd postnatal week when sudden, unexpected, and significant neurochemical, metabolic, ventilator, and electrophysiological changes occur in normal animals, and when their responses to hypoxia are at their weakest. During this time, the system is under much greater inhibition than excitation measurable at the cellular and electrophysiological levels. The evidence of such a critical period of normal postnatal development has significant relevance to the understanding of SIDS.
A third area of interest is the effect of near-infrared (NIR) light on energy metabolism in neurons. NIR has been known to promote wound healing, but its mechanism is poorly understood. It turns out that cytochrome c oxidase with copper centers is a key photoacceptor in the NIR range. When we treated cultured primary neurons poisoned by various toxins with NIR, their energy levels returned toward normal and the incidence of apoptosis was drastically reduced. Currently, we are probing the mechanisms further with both in vivo and in vitro approaches. The goal is that NIR may rescue neurons partially damaged by diseases, such as Parkinson's Disease.
Our long-term goal is to unravel some of the molecular mechanisms related to metabolic and neurochemical abnormalities in human neurological and mitochondrial diseases.