title: Proteasome inhibition alters neural mitochondrial homeostasis and mitochondria turnover.
abstract: Inhibition of proteasome activity occurs in normal aging and in a wide variety of neurodegenerative conditions including Alzheimer's disease and Parkinson's disease. Although each of these conditions is also associated with mitochondrial dysfunction potentially mediated by proteasome inhibition, the relationship between proteasome inhibition and the loss of mitochondrial homeostasis in each of these conditions has not been fully elucidated. In this study, we conducted experimentation in order to begin to develop a more complete understanding of the effects proteasome inhibition has on neural mitochondrial homeostasis. Mitochondria within neural SH-SY5Y cells exposed to low level proteasome inhibition possessed similar morphological features and similar rates of electron transport chain activity under basal conditions as compared with untreated neural cultures of equal passage number. Despite such similarities, maximal complex I and complex II activities were dramatically reduced in neural cells subject to proteasome inhibition. Proteasome inhibition also increased mitochondrial reactive oxygen species production, reduced intramitochondrial protein translation, and increased cellular dependence on glycolysis. Finally, whereas proteasome inhibition generated cells that consistently possessed mitochondria located in close proximity to lysosomes with mitochondria present in the cellular debris located within autophagosomes, increased levels of lipofuscin suggest that impairments in mitochondrial turnover may occur following proteasome inhibition. Taken together, these data demonstrate that proteasome inhibition dramatically alters specific aspects of neural mitochondrial homeostasis and alters lysosomal-mediated degradation of mitochondria with both of these alterations potentially contributing to aging and age-related disease in the nervous system.
authors.affiliation: Department of Anatomy and Neurobiology, 205 Sanders-Brown Building, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Sullivan
authors.forename: Natasa B
authors.initials: NB
authors.lastname: Dragicevic
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Deng
authors.forename: Yidong
authors.initials: Y
authors.lastname: Bai
authors.forename: Edgardo
authors.initials: E
authors.lastname: Dimayuga
authors.forename: Qunxing
authors.initials: Q
authors.lastname: Ding
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Chen
authors.forename: Annadora J
authors.initials: AJ
authors.lastname: Bruce-Keller
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Keller
mesh_terms: D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases; D004579:Electron Transport; D004734:Energy Metabolism; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D009097:Multienzyme Complexes; D017382:Reactive Oxygen Species; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex