The mitochondrial thioredoxin system regulates nitric oxide-induced HIF-1α protein

Hypoxia-inducible factor-1 (HIF-1), consisting of two subunits, HIF-1α and HIF-1β, is a key regulator for adaptation to low oxygen availability, i.e., hypoxia. Compared to the constitutively expressed HIF-1β, HIF-1α is regulated by hypoxia but also under normoxia (21% O2) by several stimuli, including nitric oxide (NO). In this study, we present evidence that overexpression of mitochondrial-located thioredoxin 2 (Trx2) or thioredoxin reductase 2 (TrxR2) attenuated NO-evoked HIF-1α accumulation and transactivation of HIF-1 in HEK293 cells. In contrast, cytosolic-located thioredoxin 1 (Trx1) enhanced HIF-1α protein amount and activity under NO treatments. Taking into consideration that thioredoxins affect the synthesis of HIF-1α by altering Akt/mTOR signaling, we herein show that p42/44 mitogen-activated protein kinase and p70S6 kinase are involved. Moreover, intracellular ATP was increased in Trx1-overexpressing cells but reduced in cells overexpressing Trx2 or TrxR2, providing thus an understanding of how protein synthesis is regulated by thioredoxins.