Biological organisms produce a number of reactive oxygen species and other reactive chemical species (RS). Oxidative stress induced by RS contributes to injury in stroke, heart disease, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Most RS are produced by mitochondria as a byproduct of metabolism. Mitochondria-produced RS are removed from cells by antioxidant mechanisms. Excess production or decreased removal can lead to oxidative stress. A considerable amount is known about regulation of mechanisms for removing RS. Much less is known about regulation of RS production by mitochondria. The purpose of this application is to investigate a novel mechanism for regulating production of mitochondrial RS in neurons. The findings from the proposed experiments may aid in understanding oxidative stress in many other tissues as well. Our lab studies mechanisms underlying RS production and clearance in the nervous system and the role of RS in neuronal apoptosis and neurodegenerative diseases. Our preliminary and published data show that both healthy and apoptotic neurons with higher concentrations of the pro-apoptotic protein Bax have higher RS levels than do neurons with lower Bax concentrations and that Bax deletion prevents oxidative stress in the aging mouse brain and other organs. Our overall objective in this project is to understand the role of Bax and other molecular components of apoptosis in generating oxidative stress in the nervous system. Based on our preliminary and published data as well as that of others, we hypothesize that Bax has pro-oxidant effects in both apoptotic and non- apoptotic neurons primarily via a Bax-enabled caspase cleavage of components of the mitochondrial respiratory chain. Such cleavage can lead to increased RS production by augmenting leaking of electrons from the chain.
Specific aim 1 will determine the mechanisms by which Bax contributes to RS production in cortical neurons in cell culture. We will concentrate on a role for caspase-mediated damage to mitochondrial respiratory complexes.
Specific aim 2 will determine which cell types in the aging mouse brain are subject to Bax-induced oxidative stress and determine how Bax and caspases contribute to this stress. The outlined experiments will further our long-term goals of understanding mechanisms underlying RS-induced damage in the nervous system and of identifying ways to lessen this damage in neuro- and other pathologies.
Oxidative stress increases in the brain and other tissues with age and can contribute to the damage occurring in cardiovascular illnesses, stroke, neurodegenerative diseases and other pathologies. This application will elucidate a major mechanism underlying increased oxidative stress in the aging brain. This information may lead to the development of therapies that counteract the deleterious effects of oxidative stress.
| McManus, Meagan J; Franklin, James L (2018) Dissociation of JNK Activation from Elevated Levels of Reactive Oxygen Species, Cytochrome c Release, and Cell Death in NGF-Deprived Sympathetic Neurons. Mol Neurobiol 55:382-389 |
