Vitamin C Controls Neuronal Necroptosis Under Oxidative Stress

Luciano Ferrada,Katterine Salazar,Peter Vandenabeele,Francisco Nualart

doi:10.2139/ssrn.3396503

Abstract

Under physiological conditions, vitamin C is the main antioxidant found in the central nervous system and is found in two states: reduced as ascorbic acid (AA) and oxidized as dehydroascorbic acid (DHA). However, under pathophysiological conditions, AA is oxidized to DHA. The oxidation of AA and subsequent production of DHA in neurons are associated with a decrease in GSH concentrations, alterations in glucose metabolism and neuronal death. To date, the endogenous molecules that act as intrinsic regulators of neuronal necroptosis under conditions of oxidative stress are unknown. Here, we show that treatment with AA regulates the expression of pro- and antiapoptotic genes. Vitamin C also regulates the expression of RIPK1/MLKL, whereas the oxidation of AA in neurons induces morphological alterations consistent with necroptosis and MLKL activation. The activation of necroptosis by AA oxidation in neurons results in bubble formation, loss of membrane integrity, and ultimately, cellular explosion. These data suggest that necroptosis is a target for cell death induced by vitamin C.

Highlights

The reduced form of vitamin C, ascorbic acid (AA), is the main antioxidant found in the central nervous system [1]
When AA oxidation was induced in N2a cells, subcellular vitamin C transporter redistribution was observed: GLUT1 was detected in the perinuclear compartment, while SVCT2 was primarily observed near the plasma membrane (Fig. 1D)
Several antioxidants have been used to prevent cell death, our model suggests that the antioxidant function of AA does not impact neuronal necroptosis because inhibition of ROS by NAC does not prevent neuronal death, which is similar to the results described by other research groups [20,29]

Summary

Introduction

The reduced form of vitamin C, ascorbic acid (AA), is the main antioxidant found in the central nervous system [1]. It has been thought that vitamin C could act as a pro-oxidant and kill tumor cells [9,10,11]. In this context, it was recently proposed that DHA could induce cell death directly in KRAS and BRAF mutant colorectal cells [12] and in neuronal cells by triggering metabolic crisis [3,13]. New and emerging forms of regulated cell death with morphological characteristics of necrotic disintegration, including ferroptosis [17,18] and necroptosis [19,20], have been recently reported

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Results

Conclusion