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  • In addition to removing proteins and organelles related

    2022-01-17

    In addition to removing proteins and organelles related to iron and lipid metabolism, an alternative mechanism by which autophagy alizarin sale promotes ferroptosis is through the formation of the BECN1-solute carrier family 7 member 11 (SLC7A11) complex [42,43]. SLC7A11 is the main component of the antiporter system xc−, which imports the amino alizarin sale cysteine (the oxidized form of cysteine) into cells to produce the main endogenous intracellular antioxidant glutathione. Glutathione is required for GPX4 activity in the inhibition of lipid peroxidation and ferroptosis. AMP-activated protein kinase (AMPK) is an energy sensor that maintains autophagy and cellular homeostasis. Notably, AMPK is not only required for lipophagy by the phosphorylation of PLIN2 [44], but also promotes phosphorylation of BECN1, which contributes to the formation of the BECN1-SLC7A11 complex and subsequent lipid peroxidation in ferroptosis [43]. Moreover, Tat-beclin-1, a cell-permeable BECN1-derived autophagy-inducing peptide [45], can induce autophagy-dependent cell death and ferroptosis in cancer or tissue injury [43,46]. These findings reinforce the notion that ferroptosis is a type of autophagic cell death.
    Conflicts of interest
    Acknowledgments We thank Dave Primm (Department of Surgery, University of Texas Southwestern Medical Center) for his critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health (R01CA160417 [D.T.] and R01CA211070 [R.K.]), the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD [D.T.]), the Natural Science Foundation of Jilin Province of China (20160101062JC [E.D.]), the Health Foundation of the Finance Department of Jilin Province (sczsy201516 [E.D.]), and the National Natural Science Foundation of China (30870355 and 81370497 [E.D.]).
    Introduction Epidemiological studies revealed that combined exposure to paraquat and maneb in humans strongly increases the risk of Parkinson’s disease (PD), the second most common neurodegenerative disease (Costello et al., 2009; Wang et al., 2011). Chronic administration of paraquat and maneb to rodents recapitalizes many key features of PD, including motor deficits and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (Che et al., 2018; Uversky, 2004). Structurally, paraquat is similar to 1-methyl-4-phenylpyridinium ion (MPP+), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), preferentially targets the nigrostriatal pathway in the brain (Shimizu et al., 2001). Maneb can also damage dopaminergic neurons and a synergistic neurotoxicity is observed when co-administrated with paraquat (Choi and Xia, 2014; Zhou et al., 2004). Accumulating evidence suggested that NADPH oxidase, a family of superoxide-producing enzymes, plays a critical role in paraquat and maneb-induced dopaminergic neurotoxicity (Che et al., 2018; Kumar et al., 2016). We recently reported that paraquat and maneb intoxication is capable of stimulating the activation of NADPH oxidase in vitro and in vivo (Hou et al., 2018b, a). Similar to our findings, NADPH oxidase is also activated by paraquat and maneb in rat polymorphs (Shukla et al., 2015). Furthermore, genetic deletion of p47phox, the cytosolic subunit of NADPH oxidase 2, has been shown to be able to attenuate paraquat and maneb-induced NADPH oxidase activation, α-synuclein aggregation and dopaminergic neurodegeneration (Ingelsson, 2016; Kumar et al., 2016). These results suggested that the activation of NADPH oxidase contributes to paraquat and maneb-induced dopaminergic neurodegeneration. However, the potential mechanisms remain unclear. Ferroptosis is a recently recognized form of regulated cell death that is highly dependent on accumulation of iron and the production of reactive oxygen species (ROS) (Stockwell et al., 2017; Xie et al., 2016). Although ferroptosis was initially identified as a non-apoptotic cell death in oncogenic harvey-RAS viral oncogene homolog (HRAS)-containing cancer cell lines (Yagoda et al., 2007), subsequent studies revealed a clear potential for ferroptosis as a key mode of neurodegeneration in multiple neurodegenerative diseases, including PD (Xie et al., 2016; Zhang et al., 2018). Iron accumulation is observed in the SN in PD patients (Ayton and Lei, 2014). Mutations of transferrin, a critical protein for neuronal iron uptake, are associated with increased susceptibility to PD (Rhodes et al., 2014). Furthermore, iron chelators and Ferrostatin-1 derivatives reduce degeneration of dopaminergic neurons in experimental PD models induced by MPTP (Do Van et al., 2016). However, whether NADPH oxidase mediates dopaminergic neurotoxicity through ferroptosis remain to be investigated.