Abstract |
Aluminum (Al), a known environmental pollutant, has been linked to numerous pathologies such as Alzheimer's disease and anaemia. In this study, we show that alpha-ketoglutarate (KG) mitigates the Al-mediated nuclear accumulation of hypoxia inducible factor-1alpha (HIF-1alpha) in cultured human hepatocytes (HepG2). The nuclear localization of HIF-1alpha appeared to be triggered by the Al-induced perturbation of prolyl hydroxylase 2 (PHD2). This enzyme was markedly diminished in the Al-challenged hepatocytes. The fate of PHD2 and HIF-1alpha was intricately linked to the mitochondrial dysfunction observed during Al stress. BN-PAGE, immunoblot, and HPLC revealed that the loss of alpha-ketoglutarate dehydrogenase (KGDH) and succinate dehydrogenase (SDH) activities were coupled to the accumulation of succinate. However, the treatment of the Al-stressed cells with KG recovered the activity and expression of KGDH, SDH, and PHD2 with a concomitant decrease in the levels of HIF-1alpha in the nucleus. Taken together, these data indicate that the homeostasis of KG plays a pivotal role in aerobic and anaerobic respiration.
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Authors | Ryan J Mailloux, Simone Puiseux-Dao, Vasu D Appanna |
Journal | Biochimie
(Biochimie)
Vol. 91
Issue 3
Pg. 408-15
(Mar 2009)
ISSN: 1638-6183 [Electronic] France |
PMID | 19028544
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Culture Media, Serum-Free
- Hypoxia-Inducible Factor 1, alpha Subunit
- Indicators and Reagents
- Ketoglutaric Acids
- Propidium
- Hydrogen Peroxide
- Aluminum
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Topics |
- Aluminum
(metabolism, toxicity)
- Carcinoma, Hepatocellular
(metabolism, pathology)
- Cell Line, Tumor
- Cell Nucleus
(genetics, metabolism)
- Cell Survival
(drug effects)
- Culture Media, Serum-Free
- Hepatocytes
(metabolism)
- Humans
- Hydrogen Peroxide
(analysis, metabolism)
- Hypoxia-Inducible Factor 1, alpha Subunit
(genetics, metabolism)
- Indicators and Reagents
(metabolism)
- Ketoglutaric Acids
(metabolism)
- Liver Neoplasms
(metabolism, pathology)
- Models, Biological
- Propidium
(metabolism)
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