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

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.