The maintenance of well-functioning mitochondria plays a key role in neuronal health. In the previous project period, we found that neuronal injury in several neurotoxin and genetic models of parkinsonian neurodegeneration converged on eliciting increased mitochondrial turnover by autophagy (mitophagy). While mitophagy in some models is neuroprotective, in other models, inhibiting autophagy reduces neurite retraction and cell death. We hypothesize that the capacity to replace damaged/degraded mitochondria through mitochondrial biogenesis is important in determining survival-death outcomes in this context. Preliminary data indicate a key role for extracellular signal-regulated protein kinase 2 (ERK2), which shows an altered mitochondrial distribution in Parkinson's disease midbrain neurons, in regulating both mitophagy and mitochondrial biogenesis. We will utilize differentiated neuroblastoma cells, primary embryonic mouse neurons and in vivo mouse models to study the mechanism(s) leading to the observed decreases in mitochondrial content and function, study the role of phosphorylation in regulating biogenesis, and determine the neuroprotective potential for strategies to modulate mitochondrial content in toxin and dominant genetic models of Parkinson's disease.
Mitochondria represent the primary source of energy within brain cells (neurons). While removing damaged mitochondria can be beneficial, excessive loss of mitochondria also contributes to neurodegeneration in several models of Parkinson's disease. We will determine why these injuries reduce mitochondrial content, and whether enhancing the ability of neuronal cells to rebuild new mitochondria promotes beneficial effects of mitochondrial recycling.
|Verma, Manish; Callio, Jason; Otero, P Anthony et al. (2017) Mitochondrial Calcium Dysregulation Contributes to Dendrite Degeneration Mediated by PD/LBD-Associated LRRK2 Mutants. J Neurosci 37:11151-11165|
|Gusdon, Aaron M; Callio, Jason; Distefano, Giovanna et al. (2017) Exercise increases mitochondrial complex I activity and DRP1 expression in the brains of aged mice. Exp Gerontol 90:1-13|
|Kagan, V E; Jiang, J; Huang, Z et al. (2016) NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy. Cell Death Differ 23:1140-51|
|Banerjee, Kalpita; Munshi, Soumyabrata; Xu, Hui et al. (2016) Mild mitochondrial metabolic deficits by ?-ketoglutarate dehydrogenase inhibition cause prominent changes in intracellular autophagic signaling: Potential role in the pathobiology of Alzheimer's disease. Neurochem Int 96:32-45|
|Di Maio, Roberto; Barrett, Paul J; Hoffman, Eric K et al. (2016) ?-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease. Sci Transl Med 8:342ra78|
|Ravi, Sreeram; Peña, Karina A; Chu, Charleen T et al. (2016) Biphasic regulation of lysosomal exocytosis by oxidative stress. Cell Calcium 60:356-362|
|Gusdon, Aaron M; Fang, Fang; Chen, Jing et al. (2015) Association of the mt-ND2 5178A/C polymorphism with Parkinson's disease. Neurosci Lett 587:98-101|
|Au, Alicia K; Chen, Yaming; Du, Lina et al. (2015) Ischemia-induced autophagy contributes to neurodegeneration in cerebellar Purkinje cells in the developing rat brain and in primary cortical neurons in vitro. Biochim Biophys Acta 1852:1902-11|
|Bueno, Marta; Lai, Yen-Chun; Romero, Yair et al. (2015) PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J Clin Invest 125:521-38|
|Steer, Erin K; Dail, Michelle K; Chu, Charleen T (2015) Beyond mitophagy: cytosolic PINK1 as a messenger of mitochondrial health. Antioxid Redox Signal 22:1047-59|
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