Our nervous system is the primary organ by which we sense, interpret, remember, and respond to the outside world and to our own internal physiology. This elaborate system of neurons functions as a communication network, with vast arrays of chemical and electrical synapses between individual neuronal cells. The nervous system also interfaces with other tissues of the body, either directly (e.g., neuromuscular junctions at skeletal muscles) or indirectly (e.g., the release of hormones, biogenic amine neurotransmitters, and neuropeptides into the blood stream), to regulate physiology and behavior, as well as maintain overall body homeostasis. Unlike many bodily tissues, the nervous system is largely incapable of replacing damaged cells once development is complete, making it susceptible to traumatic injury and age-associated decline. The high energy demands of electrochemical signaling, combined with the inability to store energy in the form of glycogen reserves, makes neurons highly dependent on oxygen, oxidative phosphorylation, and mitochondria. The nervous system has evolved multiple mechanisms to maximize mitochondrial function and prevent damage from acute oxygen starvation. Indeed, the underlying etiology of many neurological disorders and diseases, including ischemic stroke, Parkinson’s Disease, and Alzheimer’s Disease, are due to defects in one or more of these key neurophysiological processes.

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Environment can impact nervous system function, and neurons can respond to accommodate a changing environment. Specifically, oxygen influences behavior in many organisms, and low oxygen levels (hypoxia) can have devastating consequences for neuron survival due to excitotoxicity from overactivated neurotransmitter receptors and impaired mitochondrial function. We have shown that hypoxia blocks the membrane recycling of glutamate-gated ion channels to synapses, thereby depressing glutamatergic signaling. Surprisingly, HIF-1, which is the canonical transcription factor that mediates most cellular hypoxia responses, does not mediate this effect. Instead, a specific isoform of the prolyl hydroxylase EGL-9, a key sensor for oxygen, recruits LIN-10, a known PDZ scaffolding protein, to endosomes, where together the two proteins promote glutamate receptor recycling. This is a novel way by which animals can sense and respond to oxygen levels, and it suggests that the protective mechanisms are more diverse than originally appreciated.  A complete understanding of the hypoxia response pathway (i.e., EGL-9 and HIF-1) is important for understanding ischemic stroke. In addition, this pathway has become a target of interest for new chemotherapeutics, as HIF-1 is activated and plays a key role in cancer progression and metastasis.

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In addition to being the “powerhouse of the cell,” mitochondria play critical roles in mediating calcium buffering, apoptosis, and necrosis. They are also a major source of reactive oxygen species (ROS), which can have both a signaling role and be damaging to cells. Mitochondria are actively transported within neurons to synapses, and damaged mitochondria – a potential threat to the cell – are transported back to the cell body for removal by mitophagy. Mitochondria are also dynamic, undergoing fusion and fission. Fusion is thought to be a mechanism for boosting mitochondrial output and protecting mitochondrial health, whereas fission is thought to be the first step on the way to mitophagy and the removal of damaged mitochondria. Defects in mitochondrial dynamics have a clear role in Parkinson’s Disease. Defects in mitochondrial transport have a clear role in Alzheimer’s Disease. Thus, an understanding of mitochondrial dynamics and transport is important for our understanding of neurological disorders with mitochondrial etiology, as well as our understanding of aging and age-associated diseases. Mitochondrial dynamics as a field has largely been studied in single celled yeast; thus, little is known about the machinery that conducts mitochondrial fission and fusion in specialized tissues like neurons. We are studying mitochondrial dynamics in C.

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