Aluminum toxicity elicits a dysfunctional TCA cycle and succinate accumulation in hepatocytes.
Aluminum (Al), a known environmental toxicant, has been linked to a variety of pathological conditions such as dialysis dementia, osteomalacia, Alzheimer's disease, and Parkinson's disease. However, its precise role in the pathogenesis of these disorders is not fully understood. Using hepatocytes as a model system, we have probed the impact of this trivalent metal on the aerobic energy-generating machinery. Here we show that Al-exposed hepatocytes were characterized by lipid and protein oxidation and a dysfunctional tricarboxylic acid (TCA) cycle. BN-PAGE, SDS-PAGE, and Western blot analyses revealed a marked decrease in activity and expression of succinate dehydrogenase (SDH), alpha-ketoglutarate dehydrogenase (KGDH), isocitrate dehydrogenase-NAD+ (IDH), fumarase (FUM), aconitase (ACN), and cytochrome c oxidase (Cyt C Ox). 13C-NMR and HPLC studies further confirmed the disparate metabolism operative in control and Al-stressed cells and provided evidence for the accumulation of succinate in the latter cultures. In conclusion, these results suggest that Al toxicity promotes a dysfunctional TCA cycle and impedes ATP production, events that may contribute to various Al-induced abnormalities.
Mailloux
Ryan J
RJ
Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario, Canada, P3E 2C6.
Hamel
Robert
R
Appanna
Vasu D
VD
D000535:Aluminum / Q000633:toxicity*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D002952:Citric Acid Cycle / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D019802:Succinic Acid / Q000378:metabolism*
D019802:Succinic Acid; D000535:Aluminum