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  • br Significance Metabolites present in

    2022-06-21


    Significance Metabolites present in the extracellular environment can potently modulate cellular phenotypes and potentially serve as therapeutics for various diseases. Ferroptosis is a non-apoptotic cell death process characterized by the generation of toxic lipid reactive oxygen species (ROS). In this study we report that exogenous monounsaturated fatty acids (MUFAs) can promote a ferroptosis-resistant cellular state characterized by reduced total levels of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) and reduced sensitivity to oxidation of the lipid ROS probe C11 BODIPY 581/591 at the plasma membrane. The ability of exogenous MUFAs to inhibit ferroptosis and suppress lipid ROS accumulation at the plasma membrane requires the free fatty acid-activating enzyme, ACSL3. We propose that non-oxidizable MUFAs displace oxidizable PUFAs from membrane phospholipids, thereby limiting the sensitivity of the membrane to PUFA-dependent oxidation. Exogenous MUFAs also suppress apoptotic lipotoxicity triggered by the accumulation of saturated fatty acids (SFAs), but this protective effect is less dependent on ACSL3. Thus, exogenous MUFAs can inhibit both ferroptosis and lipotoxicity, but through distinct mechanisms. This study suggests that variation in environmental lipid levels and the inherent competition between individual PUFA, MUFA, and SFA species for incorporation into membrane lipids shapes the cell state and sensitivity to both non-apoptotic and apoptotic cell death.
    STAR★Methods
    Introduction The molecular and biochemical basis of neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases is characterized by mitochondrial dysfunction, a reduction in glutathione (GSH), and abnormal metabolism of free iron (Dias et al., 2013; Schulz et al., 2000; Smeyne and Smeyne, 2013). Abnormalities in mitochondrial function and alterations in GSH and free iron status might cause oxidative stress and contribute to cascading neuronal cell death and the progressive nature of such diseases (Halliwell, 2006). Cellular models of endogenous oxidative stress such as glutamate-induced oxytosis in mouse hippocampal HT22 Terbinafine (Tan et al., 2001) and erastin-induced ferroptosis in some cancer cells (Dixon et al., 2014) are an iron-dependent form of non-apoptotic cell death and reproduce many of the aforementioned characteristics. It later became apparent that oxytosis and ferroptosis are highly similar if not identical (Lewerenz et al., 2018). Mitochondrial impairment induced by oxytosis and ferroptosis is characterized by the presence of fragmented mitochondria and loss of the mitochondrial membrane potential in HT22 cells (Jelinek et al., 2018; Pfeiffer et al., 2014). In these cells, high concentrations of extracellular glutamate or erastin inhibit the glutamate-cystine antiporter in the plasma membrane, leading to depletion of intracellular GSH, accumulation of reactive oxygen species (ROS) and a detrimental influx of calcium at the end of the cell death cascade (Tan et al., 1998; Yang et al., 2014). Because HT22 cells lack functional ionotropic glutamate receptors, excitotoxicity can be excluded as a cause for glutamate receptor-mediated cell death that is triggered by Ca2+ influx (Maher and Davis, 1996). Glutamate-induced oxidative cell death has been described not only in neuronal cell lines but also in primary neuronal cultures (Li et al., 1997) and oligodendrocytes (Oka et al., 1993). Oxidative stress results in direct or indirect ROS-mediated activation of various intracellular signaling pathways. ROS can activate apoptosis signaling-regulated kinase 1 (ASK1), which in turn phosphorylates the stress kinases such as p38 MAPK and JNK to promote apoptosis (Ray et al., 2012). The compromised MAPK signaling pathways contribute to the pathology of diverse human diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (Kim and Choi, 2015). Oxidative stress also affects double-stranded RNA-dependent protein kinase (PKR), initially identified and characterized as a translational inhibitor in an antiviral pathway activated by interferons (Gourmaud et al., 2016; Mouton-Liger et al., 2012). As a vital component of the cellular antiviral response pathway, PKR is autophosphorylated and activated on binding to dsRNA, resulting in the inhibition of protein synthesis via the phosphorylation of eIF2α. Although the inflammation kinase PKR promotes cellular protection against infection, several studies have reported that PKR stimulates not only eIF2α but also MAPK signaling pathways including p38 MAPK and JNK in response to a variety of stimuli (Nakamura et al., 2010; Williams, 1999). PKR activation has also been reported in neurological diseases including Alzheimer’s, Parkinson’s and Huntington’s diseases (Bando et al., 2005; Onuki et al., 2004; Peel and Bredesen, 2003). Recently, Reimer et al. demonstrated a pro-degenerative role of activated PKR in an α-synuclein-dependent cell model of multiple system atrophy, where inhibition and silencing of PKR decrease cellular degeneration and block the increase in caspase-3 activity (Reimer et al., 2018). However, little is known about whether PKR signaling is involved in oxytosis and ferroptosis in which caspase-3 activation, nuclear and DNA fragmentation and chromatin condensation, hallmarks of classical apoptosis, did not occur (Linkermann et al., 2014; Tan et al., 2001).