Minimal Peroxide Exposure of Neuronal Cells Induces Multifaceted Adaptive Responses

Wayne Chadwick,Nicholas Mitchell,Kevin G Becker,Matthew D Stone,Yu Zhou,Stuart Maudsley,Liyun Wang,Bronwen Martin,Sung-Soo Park,Adrian Harwood

doi:10.1371/journal.pone.0014352

Abstract

Oxidative exposure of cells occurs naturally and may be associated with cellular damage and dysfunction. Protracted low level oxidative exposure can induce accumulated cell disruption, affecting multiple cellular functions. Accumulated oxidative exposure has also been proposed as one of the potential hallmarks of the physiological/pathophysiological aging process. We investigated the multifactorial effects of long-term minimal peroxide exposure upon SH-SY5Y neural cells to understand how they respond to the continued presence of oxidative stressors. We show that minimal protracted oxidative stresses induce complex molecular and physiological alterations in cell functionality. Upon chronic exposure to minimal doses of hydrogen peroxide, SH-SY5Y cells displayed a multifactorial response to the stressor. To fully appreciate the peroxide-mediated cellular effects, we assessed these adaptive effects at the genomic, proteomic and cellular signal processing level. Combined analyses of these multiple levels of investigation revealed a complex cellular adaptive response to the protracted peroxide exposure. This adaptive response involved changes in cytoskeletal structure, energy metabolic shifts towards glycolysis and selective alterations in transmembrane receptor activity. Our analyses of the global responses to chronic stressor exposure, at multiple biological levels, revealed a viable neural phenotype in-part reminiscent of aged or damaged neural tissue. Our paradigm indicates how cellular physiology can subtly change in different contexts and potentially aid the appreciation of stress response adaptations.

Highlights

Cellular adaptations to environmental changes are likely to be highly complex and involve many of the basic cellular functions
Ultrastructural, mitochondrial and calcium homeostatic alterations induced by chronic minimal peroxide (CMP)
Similar structural changes, compared to control cells, were seen for 10 nM (Figure 1A, 4, 5, 6) and 10 mM H2O2 (Figure 1A: panels 7, 8, 9) indicating that qualitatively similar effects were seen with the chronic minimal peroxide (CMP: 10 nM H2O2, seven day exposure) and higher peroxide doses

Summary

Introduction

Cellular adaptations to environmental changes are likely to be highly complex and involve many of the basic cellular functions. Endogenous ROS-scavenging pathways represent an antioxidant defense system, including both small molecules (tocopherols, vitamin C, glutathione, etc.) and antioxidant enzymes (the superoxide dismutases (SOD), the glutathione peroxidases, catalase) The balance between these pathways determines the absolute level of oxidative stress. High concentration (0.25 M), acute (90 minute) peroxide exposure has been shown to switch energy generation in human cells from aerobic metabolism to glycolysis. This functional energetic shift appears to be an important hallmark of aged tissues in numerous species, as proposed by the epigenetic oxidative redox shift theory of aging [18,19,20,21]. It has been shown that many other profound deficits in other receptor systems, e.g. cholinergic, serotoninergic, dopaminergic, histaminic, are implicated in aging and neurodegeneration processes [36,37,38,39]

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