Aluminum-induced Defective Mitochondrial Metabolism Perturbs Cytoskeletal Dynamics in Human Astrocytoma Cells J. Lemire, 1 R. Mailloux, 1 S. Puiseux-Dao, 2 and V. D. Appanna 1 * 1 Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario, Canada 2 USM 505/EA 4105, Ecosyste `me et interactions toxiques, De ´partment de regulations, development, et diversite ´ mole ´culaire, Muse ´um Nationale d’Histoire Naturelle, Paris, France Although aluminum (Al), a known environmental toxin, has been implicated in a variety of neurological disor- ders, the molecular mechanism responsible for these conditions is not fully understood. In this report, we demonstrate the ability of Al to trigger mitochondrial dysfunction and ineffective adenosine triphosphate (ATP) production. This situation severely affected cytos- keletal dynamics. Whereas the control cells had well- defined structures, the Al-exposed astrocytoma cells appeared as globular structures. Creatine kinase (CK) and profilin-2, two critical modulators of cellular mor- phology, were markedly diminished in the astrocytoma cells treated with Al. Antioxidants such as a-ketogluta- rate and N-acetylcysteine mitigated the occurrence of the globular-shaped cells promoted by Al toxicity. Taken together, these data reveal an intricate link between ATP metabolism and astrocytic dysfunction and provide molecular insights into the pathogenesis of Al-induced neurological diseases. V V C 2008 Wiley-Liss, Inc. Key words: aluminum; energy metabolism; ATP; creatine kinase; cytoskeletal dynamics; astrocytes All life forms rely on adenosine triphosphate (ATP) as their universal energy currency in order to perform numerous cellular tasks. The energy harnessed from ATP is used to drive protein synthesis, DNA repair, ion transport, and the maintenance of cytoskeletal structure and dynamics (Wieser and Krumschnabel, 2001; Kovar et al., 2006). ATP can be generated in a number of ways, including during anaerobic respiration via substrate level phosphorylation and aerobic respiration via oxida- tive phosphorylation (Fink, 2002; Leach et al., 2002). In most aerobic organisms, the mitochondria house the necessary enzymatic machinery and respiratory com- plexes required to synthesize ATP in an O 2 -dependent manner. While the tricarboxylic acid (TCA) cycle pro- duces the necessary reducing equivalents, NADH and FADH 2 , the respiratory complexes transfer the electrons from these moieties to the terminal electron acceptor, O 2 . This process is coupled to the formation of a H 1 gradient, which is tapped to drive ATP formation (Yoshida et al., 2001). Complex eukaryotes also rely on other sources of ATP such as phosphogens in order to sustain energy demands (Sauer and Schlattner, 2004). Highly oxidative tissues such as the human brain and skeletal muscle invoke creatine kinase (CK) to produce ATP from phosphocreatine when energy is in high demand (Saks et al., 1996). The brain consumes the most energy in the human body. Indeed, neurons rely on a steady supply of ATP in order to maintain cerebral functions. Astrocytes play a key role in supporting neuronal energy metabolism. These specialized cells also help in modulating synaptic firing and efficiency, supply trophic factors, and support the blood–brain barrier (Anderson and Swanson, 2000; Anderson and Nedergaard, 2003). The ability of astro- cytes to perform these vital functions has been attributed to their unique morphology (Derouiche et al., 2002). Indeed, the specific arrangement of the actin and inter- mediate filaments provides the critical framework neces- sary to maintain a well-defined morphology that is required for the proper functioning of the astrocytes. The maintenance of this cytoskeletal configuration is inherently dependent on ATP. The polymerization of actin relies on a steady supply of ATP (Gourlay and Ayscough, 2005). Hence, energy metabolism, cytoskele- tal structure, and neuronal function are intimately linked (Ames, 2000; Gartlon et al., 2006). Environmental stressors and toxins, such as Al, are known to limit the aerobic production of ATP, a situa- tion that may have a negative influence on astrocytic function. Al, a pro-oxidant, has also been shown to per- turb the cytoskeleton in neurons and astrocytes (Aremu *Correspondence to: V. D. Appanna, Department of Chemistry and Bio- chemistry, Laurentian University, Sudbury, Ontario, P3E 2C6, Canada. E-mail: VAppanna@laurentian.ca Received 11 August 2008; Revised 8 October 2008; Accepted 10 October 2008 Published online 15 December 2008 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/jnr.21965 Journal of Neuroscience Research 87:1474–1483 (2009) ' 2008 Wiley-Liss, Inc.