GOLPH3 Mediated Golgi Stress Response in Modulating N2A Cell Death upon Oxygen-Glucose Deprivation and Reoxygenation Injury

Abstract

Increasing evidence implicating that the organelle-dependent initiation of cell death merits further research. The evidence also implicates Golgi as a sensor and common downstream-effector of stress signals in cell death pathways, and it undergoes disassembly and fragmentation during apoptosis in several neurological disorders. It has also been reported that during apoptotic cell death, there is a cross talk between ER, mitochondria, and Golgi. Thus, we hypothesized that Golgi might trigger death signals during oxidative stress through its own machinery. The current study found that GOLPH3, an outer membrane protein of the Golgi complex, was significantly upregulated in N2A cells upon oxygen-glucose deprivation and reoxygenation (OGD/R), positioning from the compact perinuclear ribbon to dispersed vesicle-like structures throughout the cytoplasm. Additionally, elevated GOLPH3 promoted a stress-induced conversion of the LC3 subunit I to II and reactive oxygen species (ROS) production in long-term OGD/R groups. The collective data indicated that GOLPH3 not only acted as a sensor of Golgi stress for its prompt upregulation during oxidative stress but also as an initiator that triggered and propagated specific Golgi stress signals to downstream effectors. This affected ROS production and stress-related autophagy and finally controlled the entry into apoptosis. The data also supported the hypothesis that the Golgi apparatus could be an ideal target for stroke, neurodegenerative diseases, or cancer therapy through its own functional proteins.

Knockout of the Golgi stacking proteins GRASP55 and GRASP65 impairs Golgi structure and function

“…, 2013), foot-and-mouth disease (Zhou et al. , 2013), reoxygenation injury (Li et al. , 2016), and cancer (Petrosyan, 2015).…”

Cross organelle stress response disruption promotes gentamicin-induced proteotoxicity

“…Taken together, the early rise in the ATP:ADP ratio, mitochondrial-specific ROS accumulation, Drp-1-mediated mitochondrial fragmentation, and mitochondrial-ER dissociation provide clear evidence of CORE disruption before increases in either whole-cell oxidative stress or the misfolded protein load occurs. Although the signals that disrupt MAMs and CORE are disputed 60 , it is likely that organelle-specific stress is a primary trigger. This primary trigger of organelle-specific stress is further corroborated with recent descriptions of a novel form of localized mitochondrial UPR (UPR mt ), which responds to excess ROS 59,61 .…”

Golgi Structure and Function in Health, Stress, and Diseases

“…In addition to its high expression level in some cancer cells, GOLPH3 overexpression is also reported in mouse N2A cells under oxygen-glucose deprivation and reoxygenation (OGD/R), a model mimicking severe oxidative injury (Li et al 2016a). In this OGD/R model, GOLPH3 is overexpressed and forms puncta in the cytosol, which induces the formation of reactive oxygen species (ROS) and lipidation of LC3.…”

“…In this OGD/R model, GOLPH3 is overexpressed and forms puncta in the cytosol, which induces the formation of reactive oxygen species (ROS) and lipidation of LC3. Opposed to its anti-apoptotic role in cancer cells, depletion of GOLPH3 in OGD/R desensitizes the cells to apoptosis (Li et al 2016a).…”