PhD, Stanford University, Stanford, CA, 1970
Postdoctoral, University of Wisconsin, Madison, WI, 1970-71
Lab of Neurophysiology, National Institutes of Health, 1972-73
Energy metabolism is at the heart of health and disease. The brain, in particular, requires a rich and constant supply of energy through the oxidative pathway to sustain its major function: communication among neurons within the neuronal network and the control of most bodily functions. Neuronal activity and energy metabolism are tightly coupled processes. Neuronal activity controls energy metabolism, and not vice versa, under normal conditions. When neuronal activity is disrupted by disease, pathology, or experimental manipulations, neuronal energy supply and consumption will likewise be disrupted. On the other hand, when neuronal energy metabolism is perturbed, it will directly impact neuronal activity. Our laboratory has been probing this relationship at the cellular and molecular levels.
Cytochrome c oxidase (COX) is an important energy-generating enzyme that actively pumps protons for the generation of ATP in the mitochondria. It is a vital oxidative enzyme and the only one that can reduce molecular oxygen to water for the completion of oxidative metabolism. Our laboratory has capitalized on COX’s remarkable sensitivity to changes in neuronal energy demands, and documented that it is a reliable metabolic marker for neuronal activity. In the last three decades, our lab and many others in this country and abroad have shown that altering neuronal activity results in altering the activity and levels of COX, with a positive relationship between the two.
Importantly, cytochrome c oxidase is one of only four proteins in mammalian cells that are bigenomic. Its largest 3 subunits are encoded in the mitochondrial genome and form the catalytic core of the enzyme, whereas the other 10 subunits are encoded in the nuclear genome across 9 different chromosomes. Thus, it serves as an excellent model for studying bigenomic regulation of proteins. We found that three transcription factors (nuclear respiratory factor 1 [NRF-1], nuclear respiratory factor 2 [NRF-2], and the neuron-specific specificity protein 4 [Sp4]) all mediate such bigenomic regulation: each regulating all 13 subunits of COX.
If neuronal activity and energy metabolism are coupled at the cellular level, can this coupling extend to the molecular level? We found that, indeed, NRF-1, NRF-2, and Sp4 each also regulates mediators of glutamatergic neurotransmission: specifically, GluN1 (Grin1) and GluN2B (Grin2b) of the NMDA receptor and GluA2 (Gria2) of the AMPA receptor. These transcripts, plus those of COX, are all transcribed in the same transcription factory. More recently, we found that NRF-1 also regulates a major energy-consuming enzyme, Na+K+ATPase, in neurons. Thus, neurons ensure at the transcriptional level that energy generated will meet the energy needs of synaptic transmission. We are currently probing the role of one or more of these transcription factors in regulating inhibitory neurotransmitter receptor (GABAergic) genes in neurons.
Another research focus is the understanding of the mechanistic 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, ventilatory, 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. We are now probing for the role that an important neurotrophin, brain-derived neurotrophic factor (BDNF) plays in the synaptic imbalance during the critical period. 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. NIR can be considered as one of the therapeutic agents for promoting the health of injured neurons damaged by toxins or 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.
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