Minimal Peroxide Exposure of Neuronal Cells Induces Multifaceted Adaptive Responses

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.

Nuclear GIT2 Is an ATM Substrate and Promotes DNA Repair

“…1k), indicating a potential strong trophic role of GIT2 in DNA repair. As we have previously demonstrated that GIT2 expression is sensitive to both aging and reactive oxygen species exposure (32,33), we postulated that GIT2 may also play a role in maintaining DNA stability during periods of stress.…”

“…Our previous findings demonstrated that GIT2 expression is elevated in the brains of multiple mammalian species with natural aging (32,33). As DNA damage can specifically accumulate in the central nervous system with aging, we next examined the effect of GIT2 genomic suppression upon DNA damage in the brains of elderly mice.…”

“…Currently, less is known about the neuronal functions of GIT2, despite the fact that both GIT2 and GIT1 are widely expressed and have predominantly overlapping expression patterns throughout the mouse brain (31). Recently, neuronal expression of GIT2 across multiple mammalian species has been shown to be modulated by oxidative stresses associated with the aging process (32). In addition, we have recently demonstrated that GIT2 acts as a functional keystone factor in aging-related physiological processes (33).…”

Delineation of a Conserved Arrestin-Biased Signaling Repertoire In Vivo

“…RNA isolation from three individual animals in each experimental group was carried out using a Qiagen RNeasy Mini Kit (Qiagen, Inc., Valencia, CA), as described previously (Gesty-Palmer et al, 2013). RNA conversion to cDNA and subsequent hybridization with Sentrix MouseRef-8 Expression BeadChips (Illumina, San Diego, CA) was performed as described previously (Chadwick et al, 2010;Martin et al, 2012a). Microarray data were analyzed using DIANE 6.0 (http://www.…”

“…sas.com/en_us/home.html). Raw microarray data were subjected to filtering and z normalization and tested for significant changes as described previously (Chadwick et al, 2010). Initial filtering identified genes with a z-ratio of $1.50, with the z-ratio being derived from the difference between the averages of the observed gene z-scores divided by the S.D.…”