Peri-nuclear clustering of mitochondria is triggered during aluminum maltolate induced apoptosis

Issue title: Mitochondria in Alzheimer's Disease

Guest editors: Paula I. Moreirax and Catarina Oliveiray

Article type: Research Article

Authors: DeWitt, David A.^{a; b; *} | Hurd, Jennifer A.^a | Fox, Nena^b | Townsend, Brigitte E.^a | Griffioen, Kathleen J.S.^{a; c} | Ghribi, Othman^d | Savory, John^b

Affiliations: [a] Department of Biology, Liberty University, Lynchburg, VA, USA | [b] Department of Pathology, University of Virginia, Charlottesville, VA, USA | [c] Department of Pharmacology and Physiology, George Washington University, Washington, DC, USA | [d] Department of Pharmacology, University of North Dakota, Grand Forks, ND, USA | [x] Center for Neuroscience and Cell Biology, Institute of Physiology – Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal | [y] Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal

Correspondence: [*] Corresponding author: David A. DeWitt, Ph.D., Dept. of Biology, Liberty University, 1971 University Blvd., Lynchburg, VA 24502, USA. Tel.: +1 434 582 2228; Fax: +1 434 582 2488; E-mail: dadewitt@liberty.edu.

Abstract: Synapse loss and neuronal death are key features of Alzheimer's disease pathology. Disrupted axonal transport of mitochondria is a potential mechanism that could contribute to both. As the major producer of ATP in the cell, transport of mitochondria to the synapse is required for synapse maintenance. However, mitochondria also play an important role in the regulation of apoptosis. Investigation of aluminum (Al) maltolate induced apoptosis in human NT2 cells led us to explore the relationship between apoptosis related changes and the disruption of mitochondrial transport. Similar to that observed with tau over expression, NT2 cells exhibit peri-nuclear clustering of mitochondria following treatment with Al maltolate. Neuritic processes largely lacked mitochondria, except in axonal swellings. Similar, but more rapid results were observed following staurosporine administration, indicating that the clustering effect was not specific to Al maltolate. Organelle clustering and transport disruption preceded apoptosis. Incubation with the caspase inhibitor zVAD-FMK effectively blocked apoptosis, however failed to prevent organelle clustering. Thus, transport disruption is associated with the initiation, but not necessarily the completion of apoptosis. These results, together with observed transport defects and apoptosis related changes in Alzheimer disease brain suggest that mitochondrial transport disruption may play a significant role in synapse loss and thus the pathogenesis or Alzheimer's disease.

Keywords: Apoptosis, axonal transport, Alzheimer's disease, aluminum, staurosporine

DOI: 10.3233/JAD-2006-9211

Journal: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 195-205, 2006