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Calpains are Ca2+-dependent cysteine proteases; their aberrant activation is associated with several neurodegenerative diseases. The μ-calpain catalytic subunit, calpain-1, is located in the cytoplasm as well as in the mitochondria. Mitochondrial calpain-1 cleaves apoptosis-inducing factor (AIF), leading to apoptotic cell death. We have previously reported that short peptides of calpain-1 C2-like domain conjugated with cell penetrating peptide HIV-Tat (Tat-μCL) selectively inhibit mitochondrial calpain-1 and effectively prevent neurodegenerative diseases of the eye. In this study, we determined whether mitochondrial calpain-1 mediates oxytosis (oxidative glutamate toxicity) in hippocampal HT22 cells using Tat-μCL and newly generated polyhistidine-conjugated μCL peptide and compared their efficacies in preventing oxytosis. TUNEL assay and single strand DNA staining revealed that both μCL peptides inhibited glutamate-induced oxytosis. Additionally, both the peptides suppressed the mitochondrial AIF translocation into the nucleus. All polyhistidine-μCL peptides (containing 4–16 histidine residues) showed higher cell permeability than Tat-μCL. Notably, tetrahistidine (H4)-μCL exerted the highest cytoprotective activity. Thus, H4-μCL may be a potential peptide drug for calpain-1-mediated neurodegenerative diseases such as Alzheimer's disease.

The oxidative degradation of lipids has been shown to be implicated in the progression of several neurodegenerative diseases and modulating lipid peroxidation may be efficacious for treating Alzheimer’s disease (AD). This hypothesis is strengthened by recent findings suggesting that oxytosis/ferroptosis, a cell death process characterized by increased lipid peroxidation, plays an important role in AD-related toxicities. CMS121 is a small molecule developed against these aspects of neurodegeneration. Here we show that CMS121 alleviates cognitive loss, modulates lipid metabolism and reduces inflammation and lipid peroxidation in the brains of transgenic AD mice. We identify fatty acid synthase (FASN) as a molecular target of CMS121 and demonstrate that modulating lipid metabolism through the inhibition of FASN protects against several AD-related toxicities. These results support the involvement of lipid peroxidation and perturbed lipid metabolism in AD pathophysiology and propose FASN as a target in AD-associated toxicities.

The human genes for interleukin 13 (IL-13) and its receptor alpha 1 (IL-13Rα1) are in chromosomal regions associated with Parkinson's disease (PD). The interaction of IL-13 with its receptor increases the susceptibility of mouse dopaminergic neurons to oxidative stress. We identified two rare single SNPs in IL13 and IL13RA1 and measured their cytotoxic effects. rs148077750 is a missense leucine to proline substitution in IL13. It was found in individuals with early onset PD and no other known monogenic forms of the disease and is significantly linked with PD (Fisher's exact test: p-value = 0.01, odds ratio = 14.2). rs145868092 is a leucine to phenylalanine substitution in IL13RA1 affecting a residue critical for IL-13 binding. Both mutations increased the cytotoxic activity of IL-13 on human SH-SY5Y neurons exposed to sublethal doses of hydrogen peroxide, t-butyl hydroperoxide or RLS3, an inducer of ferroptosis. Our data show that both rs148077750 and rs145868092 conferred a gain-of-function that may increase the risk of developing PD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The adult heart is a post-mitotic terminally differentiated organ; therefore, beyond development, cardiomyocyte cell death is maladaptive. Heart disease is the leading cause of death in the world and aberrant cardiomyocyte cell death is the underlying problem for most cardiovascular-related diseases and fatalities. In this chapter, we will discuss the different cell death mechanisms that engage during normal cardiac development, aging, and disease states. The most abundant loss of cardiomyocytes occurs during a myocardial infarction, when the blood supply to the heart is obstructed, and the affected myocardium succumbs to cell death. Originally, this form of cell death was considered to be unregulated; however, research from the last half a century clearly demonstrates that this form of cell death is multifaceted and employees various degrees of regulation. We will explore all of the cell death pathways that have been implicated in this disease state and the potential interplay between them. Beyond myocardial infarction, we also explore the role and mechanisms of cardiomyocyte cell death in heart failure, myocarditis, and chemotherapeutic-induced cardiotoxicity. Inhibition of cardiomyocyte cell death has extensive therapeutic potential that will increase the longevity and health of the human heart., (© 2020 Elsevier Inc. All rights reserved.)

Double-stranded RNA-dependent protein kinase (PKR) is a component of signal transduction pathways mediating various stress signals including oxidative stress and endoplasmic reticulum (ER) stress and is suggested to be implicated in several neurodegenerative diseases. Cell death in neurodegenerative conditions has been linked to oxidative stress; however, the involvement of PKR in endogenous oxidative stress such as oxytosis and ferroptosis which is quite distinct from classical apoptosis remains unknown. We investigated here the effect of a PKR inhibitor C16 (an imidazole-oxindole derivative) on oxytosis and ferroptosis in cultured HT22 mouse hippocampal cells. C16 prevented glutamate- and erastin-induced cell death, reactive oxygen species accumulation, Ca 2+ influx, phosphorylation of inositol-requiring enzyme 1 (IRE1), one of the three branches of ER stress signaling and its downstream signaling components. On the other hand, C16 did not prevent oxidative stress-induced heme oxygenase-1 expression; instead, C16 activated the extracellular signal-regulated kinase pathway. The protective effect of C16 is diminished in PKR knockout HT22 cells. Real time measurements of the oxygen consumption rate and extracellular acidification rate over a long period of time leading to cell death showed that C16 partially prevented erastin-induced mitochondrial and glycolytic dysfunction. These results suggest that PKR is an important component of oxytosis and ferroptosis and the inhibition of PKR is neuroprotective against endogenous oxidative stress-induced cell death and provide an effective strategy for neuroprotection., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Ca 2+ ions play a fundamental role in cell death mediated by oxidative glutamate toxicity or oxytosis, a form of programmed cell death similar and possibly identical to other forms of cell death like ferroptosis. Ca 2+ influx from the extracellular space occurs late in a cascade characterized by depletion of the intracellular antioxidant glutathione, increases in cytosolic reactive oxygen species and mitochondrial dysfunction. Here, we aim to compare oxidative glutamate toxicity with ferroptosis, address the signaling pathways that culminate in Ca 2+ influx and cell death and discuss the proteins that mediate this. Recent evidence hints toward a role of the machinery responsible for store-operated Ca 2+ entry (SOCE), which refills the endoplasmic reticulum (ER) after receptor-mediated ER Ca 2+ release or other forms of store depletion. Pharmacological inhibition of SOCE or transcriptional downregulation of proteins involved in SOCE like the ER Ca 2+ sensor STIM1, the plasma membrane Ca 2+ channels Orai1 and TRPC1 and the linking protein Homer protects against oxidative glutamate toxicity and direct oxidative stress caused by hydrogen peroxide or 1-methyl-4-phenylpyridinium (MPP+) injury, a cellular model of Parkinson's disease. This suggests that SOCE inhibition might have some potential therapeutic effects in human disease associated with oxidative stress like neurodegenerative disorders., (Copyright © 2017 Elsevier Ltd. All rights reserved.)