Glucose plays a main role in human fibroblasts adaptation to hypoxia

Hypoxia induces severe changes in cell biology, particularly affecting energy production pathways. Although the theme has been widely investigated, particularly in transformed cells, studies of the mitochondrial bioenergetics of normal cells exposed to both prolonged hypoxic periods and low or null glucose concentration have been scarcely addressed. To evaluate the mitochondrial changes of cells exposed to the latter conditions, we set experiments in which the contribution of the mitochondrial energy production was maximized at the expenses of low glycolysis. Human fibroblasts were exposed to 1% oxygen tension, a hypoxic condition experimentally established for these cells, and grown in glucose deficient media. At variance with fibroblasts grown in 5–25 mM glucose, fibroblasts grown in glucose deficiency adapted to hypoxia by reducing only slightly the mitochondrial mass and preserving a well structured network as it occurs in normoxia. Moreover, the oxidative phosphorylation (OXPHOS) rate of the mitochondria was enhanced, due to increased OXPHOS complexes level. The master transcriptional modulator induced by hypoxia HIF-1α and BNIP3, a factor activating mitochondrial autophagy, were expressed both in the presence and in the absence of glucose, but to a lower level in the latter condition. Similarly, the microtubule-associated protein light chain 3 active fragment (LC3-II), a typical marker of autophagy, was found less expressed in glucose-free medium than in the presence of glucose. Therefore, our data show for the first time that glucose availability significantly affects the hypoxia-induced HIF-1/BNIP3 response, and in particular glucose absence results in enhancing the OXPHOS rate.