Proteasome inhibition alters neural mitochondrial homeostasis and mitochondria turnover

Patrick G. Sullivan, Natasa B. Dragicevic, Jian Hong Deng, Yidong Bai, Edgardo Dimayuga, Qunxing Ding, Qinghua Chen, Annadora J. Bruce-Keller, Jeffrey N. Keller

Research output: Contribution to journalArticle

174 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)20699-20707
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number20
DOIs
StatePublished - May 14 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Sullivan, P. G., Dragicevic, N. B., Deng, J. H., Bai, Y., Dimayuga, E., Ding, Q., Chen, Q., Bruce-Keller, A. J., & Keller, J. N. (2004). Proteasome inhibition alters neural mitochondrial homeostasis and mitochondria turnover. Journal of Biological Chemistry, 279(20), 20699-20707. https://doi.org/10.1074/jbc.M313579200