A Global Metabolic Perspective on Aluminum Toxicity in Human Astrocytes: Implications for Neurological Disorders.

摘要

Aluminum (Al) has been associated with a variety of neurological disorders such as senile plaques, Alzheimer's disease, Parkinson's disease, and encephalopathies. The molecular mechanisms that facilitate Al to be involved in these diseases have yet to be fully unravelled. Using astrocytes as a model cerebral cellular system, we have identified biochemical modules that are altered by Al toxicity. The tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) were found to be severely impeded as a consequence of Al toxicity. The inability of the cell to generate ATP in an oxidative fashion led to a dearth of energy available for cellular processes. Consequently, Al-stressed astrocytes were unable to form a filamentous actin cytoskeleton. Loss of the actin cytoskeleton due to Al challenge resulted in abnormal "globular" cellular morphology. Similar observations were reported in astrocytes subjected to hydrogen peroxide (H 2O2), a natural reactive oxygen species (ROS).;Investigation into the effects of Al and ROS on mitochondrial metabolism, helped identify a mitochondrial isoform of lactate dehydrogenase (LDH), a discovery with major implications on the brain energy budget. This LDH, under non-stressed conditions, was found to contribute to oxidative energy production. However, under Al and ROS insult it took a more prominent role as an attenuator of ROS stress through the amplified generation of the antioxidant pyruvate. The reaction of pyruvate with ROS lead to a build-up of acetate, which was fixed into lipid stores within Al and ROS-treated astrocytes. In addition, the Al and ROS-induced perturbation of the mitochondria rendered the astrocytes incapable of beta-oxidation of fatty acids. This phenomenon was exacerbated by a diminished capability of the Al and ROS-stressed astrocytes to produce L-carnitine. The loss in L-carnitine production promoted the rerouting of the antioxidant alpha-ketoglutarate (KG) toward ROS sequestration in the Al and ROS-treated astrocytes. In fact, these astrocytes became oil-generating moieties under the influence of the Al and ROS-toxicity.;The reduced capacity of astrocytes to produce energy, the loss of the actin-cytoskeletal network, the shift in metabolic networks, and the accumulation of lipids are all factors that contribute to astrocyte dysfunction. Since astrocytes are integral to the optimal functioning of the brain, these biological events may be contributing factors linking Al to neurological disorders. Hence, this global metabolic view on Al toxicity that is fuelled by a disruption of iron (Fe) homeostasis and the promotion of an oxidative environment, provides intriguing molecular insights on how this trivalent metal may contribute to neurological diseases and reveals some potential therapeutic cues on mitigating these abnormalities.