Worms, Fat, and Death: Caenorhabditis elegans Lipid Metabolites Regulate Cell Death

Caenorhabditis elegans is well-known as the model organism used to elucidate the genetic pathways underlying the first described form of regulated cell death, apoptosis. Since then, C. elegans investigations have contributed to the further understanding of lipids in apoptosis, especially the roles of phosphatidylserines and phosphatidylinositols. More recently, studies in C. elegans have shown that dietary polyunsaturated fatty acids can induce the non-apoptotic, iron-dependent form of cell death, ferroptosis. In this review, we examine the roles of various lipids in specific aspects of regulated cell death, emphasizing recent work in C. elegans.

The Role of Mitochondria in Pyroptosis

Pyroptosis is a recently discovered aspartic aspart-specific cysteine protease (Caspase-1/4/5/11) dependent mode of gene-regulated cell death cell death, which is represented by the rupture of cell membrane perforations and the production of proinflammatory mediaters like interleukin-18(IL-18) and interleukin-1β (IL-1β). Mitochondria also play an important role in apoptotic cell death. When it comes to apoptosis of mitochondrion, mitochondrial outer membrane permeabilization (MOMP) is commonly known to cause cell death. As a downstream pathological process of apoptotic signaling, MOMP participates in the leakage of cytochrome-c from mitochondrion to the cytosol and subsequently activate caspase proteases. Hence, targeting MOMP for the sake of manipulating cell death presents potential therapeutic effects among various types of diseases, such as autoimmune disorders, neurodegenerative diseases, and cancer. In this review, we highlights the roles and significance of mitochondria in pyroptosis to provide unexplored strategies that target the mitochondria to regulate cell death for clinical benefits.

Restoring Mitochondrial Function While Avoiding Redox Stress: The Key to Preventing Ischemia/Reperfusion Injury in Machine Perfused Liver Grafts?

Mitochondria sense changes resulting from the ischemia and subsequent reperfusion of an organ and mitochondrial reactive oxygen species (ROS) production initiates a series of events, which over time result in the development of full-fledged ischemia-reperfusion injury (IRI), severely affecting graft function and survival after transplantation. ROS activate the innate immune system, regulate cell death, impair mitochondrial and cellular performance and hence organ function. Arresting the development of IRI before the onset of ROS production is currently not feasible and clinicians are faced with limiting the consequences. Ex vivo machine perfusion has opened the possibility to ameliorate or antagonize the development of IRI and may be particularly beneficial for extended criteria donor organs. The molecular events occurring during machine perfusion remain incompletely understood. Accumulation of succinate and depletion of adenosine triphosphate (ATP) have been considered key mechanisms in the initiation; however, a plethora of molecular events contribute to the final tissue damage. Here we discuss how understanding mitochondrial dysfunction linked to IRI may help to develop novel strategies for the prevention of ROS-initiated damage in the evolving era of machine perfusion.

Targeting XIAP for Promoting Cancer Cell Death—The Story of ARTS and SMAC

Inhibitors of apoptosis (IAPs) are a family of proteins that regulate cell death and inflammation. XIAP (X-linked IAP) is the only family member that suppresses apoptosis by directly binding to and inhibiting caspases. On the other hand, cIAPs suppress the activation of the extrinsic apoptotic pathway by preventing the formation of pro-apoptotic signaling complexes. IAPs are negatively regulated by IAP-antagonist proteins such as Smac/Diablo and ARTS. ARTS can promote apoptosis by binding and degrading XIAP via the ubiquitin proteasome-system (UPS). Smac can induce the degradation of cIAPs but not XIAP. Many types of cancer overexpress IAPs, thus enabling tumor cells to evade apoptosis. Therefore, IAPs, and in particular XIAP, have become attractive targets for cancer therapy. In this review, we describe the differences in the mechanisms of action between Smac and ARTS, and we summarize efforts to develop cancer therapies based on mimicking Smac and ARTS. Several Smac-mimetic small molecules are currently under evaluation in clinical trials. Initial efforts to develop ARTS-mimetics resulted in a novel class of compounds, which bind and degrade XIAP but not cIAPs. Smac-mimetics can target tumors with high levels of cIAPs, whereas ARTS-mimetics are expected to be effective for cancers with high levels of XIAP.

Golgi anti-apoptotic proteins are evolutionarily conserved ion channels that regulate cell death in plants

ABSTRACTProgrammed cell death regulates developmental and stress responses in eukaryotes. Golgi anti-apoptotic proteins (GAAPs) are evolutionarily conserved cell death regulators. Human and viral GAAPs inhibit apoptosis and modulate intracellular Ca2+fluxes, and viral GAAPs form cation-selective channels. Although most mammalian cell death regulators are not conserved at the sequence level in plants, the GAAP gene family shows expansion, with five paralogues (AtGAAP1-5) in the Arabidopsis genome. We pursued molecular and physiological characterization of AtGAAPs making use of the advanced knowledge of their human and viral counterparts. Structural modeling of AtGAAPs predicted the presence of a channel-like pore, and electrophysiological recordings from purified AtGAAP3 reconstituted into lipid bilayers confirmed that plant GAAPs can function as ion channels. AtGAAP1 and AtGAAP4 localized exclusively to the Golgi within the plant cell, while AtGAAP2, AtGAAP3 and AtGAAP5 also showed tonoplastic localization. Gene expression analysis revealed differential spatial expression and abundance of transcript forAtGAAPparalogues in Arabidopsis tissues. We demonstrate that AtGAAP1-5 inhibit Bax-induced cell death in yeast. However, overexpression of AtGAAP1 induces cell death inNicotiana benthamianaleaves and lesion mimic phenotype in Arabidopsis. We propose that AtGAAPs function as Golgi-localized ion channels that regulate cell death by affecting ionic homeostasis within the cell.HighlightArabidopsis Golgi anti-apoptotic proteins (GAAPs) share functional conservation with their human and viral counterparts in cell death regulation and ion channel activityAbbreviationsAtGAAP,Arabidopsis thalianaGAAP; BI-1, Bax inhibitor-1; CFP, cyan fluorescent protein; CMLV, camelpox virus; ER, Endoplasmic reticulum; GAAP, Golgi anti-apoptotic protein; GFP, green fluorescent protein; hGAAP, human GAAP; LFG, Lifeguard; LMM, lesion mimic mutant; PCD, programmed cell death; TMBIM, transmembrane Bax inhibitor-1 motif-containing; TMDs, transmembrane domains; vGAAP, viral GAAP; YFP, yellow fluorescent protein

Emerging Roles of 5-Lipoxygenase Phosphorylation in Inflammation and Cell Death

5-Lipoxygenase (ALOX5) is an iron-containing and nonheme dioxygenase that catalyzes the peroxidation of polyunsaturated fatty acids such as arachidonic acid. ALOX5 is the rate-limiting enzyme for the biosynthesis of leukotrienes, a family of proinflammatory lipid mediators derived from arachidonic acid. ALOX5 also make great contributions to mediating lipid peroxidation. In recent years, it has been discovered that ALOX5 plays a central role in cell death including apoptosis, pyroptosis, and ferroptosis, a newly discovered type of cell death. According to the previous studies, ALOX5 can regulate cell death in two ways: one is inflammation and the other is lipid peroxidation. Meanwhile, it has been shown that ALOX5 activity is regulated by several factors including protein phosphorylation, ALOX5-interactng protein, redox state, and metal ions such as iron and calcium. In this review, we aim to summarize the knowledge on the emerging roles of ALOX5 protein phosphorylation in the regulation of cell death and inflammation in order to explore a potential target for human diseases.