Cox4i2 Triggers an Increase in Reactive Oxygen Species, Leading to Ferroptosis and Apoptosis in HHV7 Infected Schwann Cells

Abstract

Emerging evidence suggests that reactive oxygen species (ROS) play a significant role in the pathogenesis of peripheral nerve damage. Our previous study indicated that human herpesvirus 7 (HHV7) induces Bell’s palsy. However, the specific mechanism underlying the effects of ROS in HHV7 infection-induced facial nerve damage is unknown. In this study, we established a rat FN model by inoculating an HHV7 virus solution. The facial grading score and LuxolFastBlue (LFB) staining were used to assess the success of the model. Using mRNA-sequencing analysis, we found that the expression of Complex IV Subunit 4 Isoform 2 (Cox4i2) increased in infected Schwann cells (SCs). Cox4i2 was suggested to increase COX activity, thereby promoting ROS production. The changes in the endogenous oxidant and antioxidant system were assessed, and the results showed that oxidative stress increased after HHV7 infection in vivo and in vitro. However, we found that oxidative injury was relieved after the transfection of shCox4i2 in HHV7-treated SCs by evaluating cell death, cell proliferation, and the ROS level as well as the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH). Furthermore, we hypothesised that Cox4i2 loss would attenuate HHV7-induced ferroptosis and apoptosis, which are closely related to ROS in SCs. Our research illustrated that the knockdown of Cox4i2 suppresses HHV7-induced RSC96 cell ferroptosis as well as apoptosis via the ERK signalling pathway. Overall, several in vitro and in vivo methods were adopted in this study to reveal the new mechanism of ROS-induced and Cox4i2-mediated apoptosis and ferroptosis in HHV7 infected SCs.

Iron Metabolism and Ferroptosis in Peripheral Nerve Injury

“…They are deprived, for all intents and purposes, of their source for synthesis of pro-teins, lipids, and carbohydrates [29]. Then, lipid metabolism disorder, oxidative stress injury, and iron metabolism disorder in the intracellular environment lead to different kinds of cell death, such as apoptosis or ferroptosis, which further leads to nerve tissue damage and secondary nerve injury [30].…”

“…Excessive iron is capable of reacting with H 2 O 2 or HOradicals; in fact, Fe 2+ is conducive to the production of ROS, and it promotes lipid peroxidation, thereby inducing ferroptosis [41]. Bowen et al demonstrated that an increase in the cytochrome oxidase subunit 4 isoform 2 (Cox4i2) expression, which increases cytochrome oxidase (COX) activity, can promote ROS production, thereby leading to ferroptosis in human herpes virus 7-(HHV7-) infected SCs; additionally, the depletion/knock-down of Cox4i2 can suppress HHV7induced ferroptosis and apoptosis of SCs [30]. Another study has revealed that post-PNI, several proteins exhibit cellular responses to the increased levels of ROS and oxidative stress; moreover, redox-dependent metabolic processes are upregulated, indicating their involvement in the development of NP [70].…”

“…Study has reported that inhibiting the process of ferroptosis can improve the pain threshold of rats in the pathological pain model, and both ferrostatin-1 and the iron chelator could reduce neuronal degeneration in animal models [66]. Moreover, inhibition of the ferroptosis pathway has successfully alleviated oxidative nerve injury as well as mechanical or thermal hypersensitivities, thereby revealing that ferroptosis occurs in the SCs of injured tissues after PNI [30,97].…”

An update on the therapeutic implications of long-chain acyl-coenzyme A synthetases in nervous system diseases

“…Several SCs-related studies have tried to clarify the mechanism of ferroptosis in peripheral nerve injury ( Chang et al, 2021 ; Gao et al, 2022 ). Chang et al (2021) pointed out complex IV subunit 4 isoform 2 (Cox4i2) can trigger an increase in reactive oxygen species, leading to ferroptosis and apoptosis in human herpesvirus 7 (HHV7) infected SCs.…”

“…Several SCs-related studies have tried to clarify the mechanism of ferroptosis in peripheral nerve injury ( Chang et al, 2021 ; Gao et al, 2022 ). Chang et al (2021) pointed out complex IV subunit 4 isoform 2 (Cox4i2) can trigger an increase in reactive oxygen species, leading to ferroptosis and apoptosis in human herpesvirus 7 (HHV7) infected SCs. Gao et al (2022) found the overexpression of c-Jun, a key regulator of the response of SCs to peripheral nerve injury, inhibits erastin-induced ferroptosis in SCs and promotes repair of facial nerve function.…”