Strategies for Preventing Age and Neurodegenerative Disease-associated Mitochondrial Dysfunction

• Main Author: Delic, Vedad
• Format: Others
• Published: Scholar Commons 2015
• Subjects: ALS; amyloid-beta; melatonin; metabolic intermediates; metabolism; tau; Cell Biology; Molecular Biology; Neurosciences
• Online Access: http://scholarcommons.usf.edu/etd/5676; http://scholarcommons.usf.edu/cgi/viewcontent.cgi?article=6874&context=etd

Mitochondrial dysfunction plays a pivotal role in the development of aging phenotypes and aging-associated neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS). Strategies that restore mitochondrial dysfunction may rescue the deficits of central metabolism in these disorders and improve cell survival. For example, we found that modulating the mTOR signaling pathway in a tissue culture model of aging-induced mitochondrial DNA mutation enhanced mitochondrial function as evidenced by increased oxygen consumption. Our previous melatonin studies also led us to hypothesize that caloric restriction and the hormone melatonin would reverse brain mitochondrial dysfunction in animal models of AD. Although caloric restriction did not improve mitochondrial function in a transgenic P301L tau model of AD, novel insight into the regulation of F0-F1 ATP synthase activity under CR was gained that may help explain the protective effects of CR in other disease models. In addition, we determined the effects of melatonin treatment on brain mitochondrial cytochrome c oxidase (COX) activity using the transgenic APPSWE mouse model of AD bred to double melatonin receptor (MT1 and MT2) knockout mice. COX activity declined with aging in control mice, but increased with aging in AD mice, most likely as a response to mitochondrial reactive oxygen species (ROS) induced by amyloid-beta generated through APP proteolysis. Both effects were blunted by melatonin treatment. The effects of melatonin were partially dependent on the G-protein coupled melatonin receptors. We also used PD models to identify therapies that restore mitochondrial dysfunction. We showed that overexpression of wild-type alpha synuclein (α-syn) in human neuroblastoma M17 cells resulted in mitochondrial oxygen consumption deficits; similar to the levels observed when PD mutant forms (A30P α-syn, E46K α-syn, and, A53T α-syn) were overexpressed. Mitochondria from cells overexpressing α-syn were more sensitive to a high iron environment, mimicking the physiological conditions in which dopaminergic neurons are found. Diethyl oxaloacetate, succinate, and several amino acids were protective, suggesting the possibility for effective dietary interventions for PD. Lastly, we delineated the level of mitochondrial complex IV activity between gray and white matter in human cervical and lumbar spinal cord, as well as mitochondrial aggregation in the entire neurovascular units (NVU) as a consequence of ALS. At the conclusion of these projects a better understanding of the molecular mechanisms leading to mitochondrial dysfunction in AD, PD, ALS, and aging was gained and promising strategies to delay or reverse these dysfunctions were developed.