Death by necrosis

Cells suffer necrotic death when exposed to extreme environmental conditions, adverse and excessive stimuli, or when deleterious mutations are encoded in their genetic material. Unlike apoptosis, which involves a highly regulated and elaborate network of biochemical events and cascades, necrosis has been considered generally to be a chaotic decadence process that effects the inexorable demise of cells otherwise not destined to die. This grim prospect is now slowly being overturned, mostly by exciting new findings in two simple model organisms, Caenorhabditis elegans and Drosophila melanogaster. Despite the wide spectrum of necrosis-initiating conditions, evidence is accumulating that execution of necrotic or neurodegenerative cell death may be carried out by a finite common set of mechanisms. Introduction Early pioneering studies of cell death delineated two major, morphologically distinct types: apoptosis and necrosis Necrosis, the second type of cell death, is radically different from apoptosis in almost every respect. The term derives from the Greek kernel 'necros', meaning 'dead' (with a sense of dismay), and refers to the accidental death of cells exposed to extreme environmental or genetically encoded insults Injured cells undergoing necrosis display gross morphological and ultra structural features that contrast sharply with those exhibited by cells undergoing apoptosis. Death is accompanied by extensive swelling of the cell, distension of various cellular organelles, clumping and random degradation of nuclear DNA, extensive plasma membrane endocytosis and autophagy It is striking that despite the profound impact of necrotic cell death on human health, the molecular events that transpire during cellular necrosis remain obscure. The dominant concept that has permeated the field stipulated that necrotic death is merely the chaotic breakdown of a cell under intolerable conditions, involving execution mechanisms almost as diverse as the triggers initiating cell death. However, relatively recent observations in simple model organisms such as Caenorhabditis elegans and Drosophila challenge these view

Lysosomal biogenesis and function is critical for necrotic cell death in Caenorhabditis elegans

Necrotic cell death is defined by distinctive morphological characteristics that are displayed by dying cells (Walker, N.I., B.V. Harmon, G.C. Gobe, and J.F. Kerr. 1988. Methods Achiev. Exp. Pathol. 13:18–54). The cellular events that transpire during necrosis to generate these necrotic traits are poorly understood. Recent studies in the nematode Caenorhabditis elegans show that cytoplasmic acidification develops during necrosis and is required for cell death (Syntichaki, P., C. Samara, and N. Tavernarakis. 2005. Curr. Biol. 15:1249–1254). However, the origin of cytoplasmic acidification remains elusive. We show that the alkalization of endosomal and lysosomal compartments ameliorates necrotic cell death triggered by diverse stimuli. In addition, mutations in genes that result in altered lysosomal biogenesis and function markedly affect neuronal necrosis. We used a genetically encoded fluorescent marker to follow lysosome fate during neurodegeneration in vivo. Strikingly, we found that lysosomes fuse and localize exclusively around a swollen nucleus. In the advanced stages of cell death, the nucleus condenses and migrates toward the periphery of the cell, whereas green fluorescent protein–labeled lysosomal membranes fade, indicating lysosomal rupture. Our findings demonstrate a prominent role for lysosomes in cellular destruction during necrotic cell death, which is likely conserved in metazoans

The Thermal Stress Coping Network of the Nematode Caenorhabditis elegans

Response to hyperthermia, highly conserved from bacteria to humans, involves transcriptional upregulation of genes involved in battling the cytotoxicity caused by misfolded and denatured proteins, with the aim of proteostasis restoration. C. elegans senses and responds to changes in growth temperature or noxious thermal stress by well-defined signaling pathways. Under adverse conditions, regulation of the heat shock response (HSR) in C. elegans is controlled by a single transcription factor, heat-shock factor 1 (HSF-1). HSR and HSF-1 in particular are proven to be central to survival under proteotoxic stress, with additional roles in normal physiological processes. For years, it was a common belief that upregulation of heat shock proteins (HSPs) by HSF-1 was the main and most important step toward thermotolerance. However, an ever-growing number of studies have shown that targets of HSF-1 involved in cytoskeletal and exoskeletal integrity preservation as well as other HSF-1 dependent and independent pathways are equally important. In this review, we follow the thermal stimulus from reception by the nematode nerve endings till the activation of cellular response programs. We analyze the different HSF-1 functions in HSR as well as all the recently discovered mechanisms that add to the knowledge of the heat stress coping network of C. elegans

Selective Destabilization of Transcripts by mRNA Decapping Regulates Oocyte Maturation and Innate Immunity Gene Expression during Ageing in C. elegans

Removal of the 5′ cap structure of RNAs (termed decapping) is a pivotal event in the life of cytoplasmic mRNAs mainly catalyzed by a conserved holoenzyme, composed of the catalytic subunit DCP2 and its essential cofactor DCP1. While decapping was initially considered merely a step in the general 5′-3′ mRNA decay, recent data suggest a great degree of selectivity that plays an active role in the post-transcriptional control of gene expression, and regulates multiple biological functions. Studies in Caenorhabditis elegans have shown that old age is accompanied by the accumulation of decapping factors in cytoplasmic RNA granules, and loss of decapping activity shortens the lifespan. However, the link between decapping and ageing remains elusive. Here, we present a comparative microarray study that was aimed to uncover the differences in the transcriptome of mid-aged dcap-1/DCP1 mutant and wild-type nematodes. Our data indicate that DCAP-1 mediates the silencing of spermatogenic genes during late oogenesis, and suppresses the aberrant uprise of immunity gene expression during ageing. The latter is achieved by destabilizing the mRNA that encodes the transcription factor PQM-1 and impairing its nuclear translocation. Failure to exert decapping-mediated control on PQM-1 has a negative impact on the lifespan, but mitigates the toxic effects of polyglutamine expression that are involved in human disease

Selective Destabilization of Transcripts by mRNA Decapping Regulates Oocyte Maturation and Innate Immunity Gene Expression during Ageing in <i>C. elegans</i>

Removal of the 5′ cap structure of RNAs (termed decapping) is a pivotal event in the life of cytoplasmic mRNAs mainly catalyzed by a conserved holoenzyme, composed of the catalytic subunit DCP2 and its essential cofactor DCP1. While decapping was initially considered merely a step in the general 5′-3′ mRNA decay, recent data suggest a great degree of selectivity that plays an active role in the post-transcriptional control of gene expression, and regulates multiple biological functions. Studies in Caenorhabditis elegans have shown that old age is accompanied by the accumulation of decapping factors in cytoplasmic RNA granules, and loss of decapping activity shortens the lifespan. However, the link between decapping and ageing remains elusive. Here, we present a comparative microarray study that was aimed to uncover the differences in the transcriptome of mid-aged dcap-1/DCP1 mutant and wild-type nematodes. Our data indicate that DCAP-1 mediates the silencing of spermatogenic genes during late oogenesis, and suppresses the aberrant uprise of immunity gene expression during ageing. The latter is achieved by destabilizing the mRNA that encodes the transcription factor PQM-1 and impairing its nuclear translocation. Failure to exert decapping-mediated control on PQM-1 has a negative impact on the lifespan, but mitigates the toxic effects of polyglutamine expression that are involved in human disease

Diverse Functions of mRNA Metabolism Factors in Stress Defense and Aging of <i>Caenorhabditis elegans</i>

<div><p>Processing bodies (PBs) and stress granules (SGs) are related, cytoplasmic RNA-protein complexes that contribute to post-transcriptional gene regulation in all eukaryotic cells. Both structures contain translationally repressed mRNAs and several proteins involved in silencing, stabilization or degradation of mRNAs, especially under environmental stress. Here, we monitored the dynamic formation of PBs and SGs, in somatic cells of adult worms, using fluorescently tagged protein markers of each complex. Both complexes were accumulated in response to various stress conditions, but distinct modes of SG formation were induced, depending on the insult. We also observed an age-dependent accumulation of PBs but not of SGs. We further showed that direct alterations in PB-related genes can influence aging and normal stress responses, beyond their developmental role. In addition, disruption of SG-related genes had diverse effects on development, fertility, lifespan and stress resistance of worms. Our work therefore underlines the important roles of mRNA metabolism factors in several vital cellular processes and provides insight into their diverse functions in a multicellular organism.</p></div