Mitochondrial ascorbic acid prevents mitochondrial O-2(center dot-) formation, an event critical for U937 cell apoptosis induced by arsenite through both autophagic-dependent and independent mechanisms

作者：Guidarelli Andrea; Carloni Silvia; Balduini Walter; Fiorani Mara; Cantoni Orazio

来源：Biofactors, 2016, 42(2): 190-200.

DOI：10.1002/biof.1263

• vitamin C
• mitochondria
• superoxide
• arsenite
• autophagy
• apoptosis

A 16 h exposure of U937 cells to 2.5 mu M arsenite promotes superoxide (O2(center dot-)) formation and inhibition of the activity of aconitase, a O2(center dot-) sensitive enzyme. Both responses were abolished by the complex I inhibitor rotenone, or by the respiration-deficient phenotype. Interestingly, a similar suppressive effect was mediated by a short term pre-exposure to a low concentration of l-ascorbic acid (AA), previously shown to be actively taken up by the cells and by their mitochondria. The mitochondrial origin of O2(center dot-) was confirmed by fluorescence microscopy studies, whereas different approaches failed to detect a contribution of NADPH oxidase. Under similar conditions, arsenite induced autophagy as well as a decline in mitochondrial membrane potential resulting in delayed (48 h) apoptosis. Importantly, all these events turned out to be sensitive to treatments associated with prevention of O2(center dot-) formation, including AA, and were only partially blunted by inhibitors of autophagy. As a final note, the toxic effects mediated by O2(center dot-) were entirely dependent on its conversion to H2O2. AA-sensitive mitochondrial O2(center dot-) formation is therefore involved in autophagy and apoptosis induced by arsenite in U937 cells, although part of the lethal response appears mediated by an autophagy-independent mechanism.

• 出版日期2016-4