1. Academic Validation
  2. NOX2-derived hydrogen peroxide impedes the AMPK/Akt-mTOR signaling pathway contributing to cell death in neuronal cells

NOX2-derived hydrogen peroxide impedes the AMPK/Akt-mTOR signaling pathway contributing to cell death in neuronal cells

  • Cell Signal. 2022 Jun;94:110330. doi: 10.1016/j.cellsig.2022.110330.
Ruijie Zhang 1 Chunxiao Liu 2 Liu Yang 3 Tong Ji 3 Nana Zhang 3 Xiaoqing Dong 3 Xin Chen 3 Jing Ma 3 Wei Gao 3 Shile Huang 4 Long Chen 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China,; College of Life Sciences, Anhui Medical University, Anhui 230032, PR China.
  • 2 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China,; Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou 215009, PR China.
  • 3 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China.
  • 4 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA; Department of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA; Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA. Electronic address: [email protected].
  • 5 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China,. Electronic address: [email protected].
Abstract

Oxidative stress is closely related to the pathogenesis of Parkinson's disease (PD), a typical neurodegenerative disease. NADPH Oxidase 2 (NOX2) is involved in hydrogen peroxide (H2O2) generation. Recently, we have reported that treatment with H2O2 and PD toxins, including 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenylpyridin-1-ium (MPP+) and rotenone, induces neuronal Apoptosis by inhibiting the mTOR pathway. Here, we show that treatment with 6-OHDA, MPP+ or rotenone induced H2O2 generation by upregulating the levels of NOX2 and its regulatory proteins (p22phox, p40phox, p47phox, p67phox, and Rac1), leading to apoptotic cell death in PC12 cells and primary neurons. Inhibition of NOX2 with apocynin or diphenyleneiodonium, or knockdown of NOX2 powerfully attenuated PD toxins-evoked NOX2 and H2O2, thereby hindering activation of AMPK, inhibition of Akt/mTOR, and induction of Apoptosis in neuronal cells. Pretreatment with catalase, a H2O2-scavenging Enzyme, blocked the effects of PD toxins on NOX2-dependent H2O2 production, AMPK/Akt/mTOR signaling and Apoptosis in the cells. Similar effects were also seen in the cells pretreated with Mito-TEMPO, a mitochondria-selective superoxide scavenger, implying a mitochondrial H2O2-dependent mechanism involved. Further research revealed that ectopic expression of constitutively active Akt or dominant negative AMPKα, or inhibition of AMPK with compound C suppressed PD toxins-induced expression of NOX2 and its regulatory proteins, as well as consequential H2O2 production and Apoptosis in the cells. Taken together, these results indicate that certain PD toxins can impede the AMPK/Akt-mTOR signaling pathway leading to neuronal Apoptosis by eliciting NOX2-derived H2O2 production. Our findings suggest that neuronal loss in PD may be prevented by regulating the NOX2, AMPK/Akt-mTOR signaling and/or applying antioxidants to ameliorate oxidative stress.

Keywords

AMPK; Akt; Hydrogen peroxide; NADPH oxidase 2; Neuronal cells; mTOR.

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