Mitochondrial Biogenesis and Neuroprotection

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DESCRIPTION (provided by applicant): Nitric Oxide (NO) mediates many processes in the nervous system, including neurotransmission, synaptic plasticity, and excitotoxic neuronal injury. The long-term goal of this research is to delineate the mechanisms by which NO influences normal cellular homeostasis and survival so as to develop strategies to prevent neuronal cell death in neurological disorders. Preliminary experiments indicate that low concentrations of NO can increase mitochondrial number in primary rat dorsal root ganglia (DRG) neurons; the mechanisms of mitochondrial biogenesis in neurons are unknown but may involve NO and peroxisome proliferator-activated receptor y coactivator-1 (PGC-1) signaling pathways. In addition, it is possible that NO mediates its neuroprotective effects, in part, through the activation of PGC-1 in neurons and the execution of the mitochondrial biogenesis program. Therefore, the specific aims of this proposal are 1) to determine the effects of NO and the cGMP/protein kinase G pathway on mitochondrial number, 2) to investigate the regulation of mitochondrial biogenesis by PGC-1 and its downstream gene products, and 3) to determine if NO-mediated neuroprotection involves PGC-1 signaling in primary rat DRG neurons and differentiated PC12 cells. Experiments will involve the quantitation of mitochondria after exposure to NO donors or pharmacological inhibitors/activators of the cGMP pathway, evaluation of NO-induced changes in the expression of key mitochondrial biogenesis proteins, and inhibition or overexpression of PGC-1 to determine its role in mitochondrial biogenesis and neuroprotection. These experiments will address fundamental questions in neurobiology while revealing mechanisms of neuronal survival that could lead to new treatments for patients with neurological disorders.