Alpha-ketoglutarate abrogates the nuclear localization of HIF-1alpha in aluminum-exposed hepatocytes.

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.

• 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)

Chemical References

• Culture Media, Serum-Free
• Hypoxia-Inducible Factor 1, alpha Subunit
• Indicators and Reagents
• Ketoglutaric Acids
• Propidium
• Hydrogen Peroxide
• Aluminum

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)