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.
Mailloux
Ryan J
RJ
Department of Chemistry and Biochemistry, Laurentian University, 935 Ramsey Lake Road, Sudbury, Ontario P3E 2C6, Canada.
Puiseux-Dao
Simone
S
Appanna
Vasu D
VD
D000535:Aluminum / Q000378:metabolism* / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000032:analysis / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007202:Indicators and Reagents / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D011419:Propidium / Q000378:metabolism
D016895:Culture Media, Serum-Free; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007202:Indicators and Reagents; D007656:Ketoglutaric Acids; D011419:Propidium; D006861:Hydrogen Peroxide; D000535:Aluminum