Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Mitochondrial rhomboid parl regulates cytochrome c release during apoptosis via OPA1 dependent cristae remodeling

Mitochondrial function in hypoxic ischemic injury and influence of aging.

Neuronal cell death in the central nervous system has always been a challenging process to decipher. In normal physiological conditions, neuronal cell death is restricted in the adult brain, even in aged individuals. However, in the pathological conditions of various neurodegenerative diseases, cell death and shrinkage in a specific region of the brain represent a fundamental pathological feature across different neurodegenerative diseases. In this review, we will briefly go through the general pathways of cell death and describe evidence for cell death in the context of individual common neurodegenerative diseases, discussing our current understanding of cell death by connecting with renowned pathogenic proteins, including Tau, amyloid-beta, alpha-synuclein, huntingtin and TDP-43.

Neuronal Cell Death Mechanisms in Major Neurodegenerative Diseases

Background Sirtuins (SIRT1-7) are a family of NAD+-dependent deacetylases that catalyze post-translational modifications of proteins. Together, they respond to metabolic challenges, inflammatory signals or hypoxic/oxidative stress, and are associated with aging and longevity. The role of Sirtuins in the regulation of fertility emerged in 2003 when a defective reproductive phenotype was observed in SIRT1-null mice. Although studies on Sirtuins in reproductive biology have been increasing in the last years, a recent comprehensive update on this issue is still lacking. Objective and rationale This review is aimed to provide knowledge on the activation mechanism and cellular role of Sirtuins and to give an update of the rapid development of Sirtuin research in female and male reproduction under physiological and pathological conditions. The final goal is to assess whether strategies aimed to improve Sirtuin expression or activity could have therapeutic potential for infertility associated with polycystic ovarian syndrome (PCOS), endometriosis, diabetes, xenobiotic stress and aging. Search methods The MEDLINE database was examined for peer-reviewed original articles. The following keywords were searched: 'Sirtuin', 'ovary', 'oocyte', 'ovarian follicle', 'embryo', 'endometrium', 'sperm' and 'testis'. These keywords were combined with other search phrases relevant to the topic. Outcomes Our knowledge of Sirtuins in reproductive functions has grown exponentially over the last few years. The majority of the work carried out so far has focused on SIRT1 with a prevalence of studies on female reproduction. Numerous studies have provided evidence that down-regulation of SIRT1 is associated with physiological or pathological reduction of ovarian reserve. SIRT1 has also been shown to regulate proliferation and apoptosis in granulosa cells whereas SIRT3 was found to promote luteinisation. Biochemical modulation of Sirtuin activity has led to discoveries of the roles of SIRT1, SIRT2, SIRT3 and SIRT6 in improving the competence of oocytes grown or matured in vitro in humans and animal models. Recently, SIRT1, SIRT2 and SIRT3 have emerged as protectors of oocyte against postovulatory aging. Transgenic models provide strong evidence that SIRT1 is involved in spermatogenesis by influencing specific functions of male germ cell, Sertoli cells and Leydig cells. When our attention moves to post-fertilization events, maternally derived SIRT3 appears crucial in the protecting early embryos against stress conditions. Finally, increasing SIRT1 activity may have the potential to ameliorate fertility in PCOS, diabetes, endometriosis, xenobiotic stress and aging. Overall, these effects have been ascribed to Sirtuin-mediated regulation of energy homoeostasis, mitochondrial biogenesis, chromatin remodelling and protection against oxidative stress. Wider implications The present review provides challenges and opportunities to stimulate research and exploit Sirtuin-based signalling as diagnostic tools and potential targets for therapeutic applications in reproductive medicine.

/pdf/sirtuins-in-gamete-biology-and-reproductive-physiology-3kh5s45xhh.pdf

Sirtuins in gamete biology and reproductive physiology: emerging roles and therapeutic potential in female and male infertility.

Significance: The intrinsic apoptosis pathway is conserved from worms to humans and plays a critical role in the normal development and homeostatic control of adult tissues. As a result, numerous diseases from cancer to neurodegeneration are associated with either too little or too much apoptosis. Recent Advances: B cell lymphoma-2 (BCL-2) family members regulate cell death, primarily via their effects on mitochondria. In stressed cells, proapoptotic BCL-2 family members promote mitochondrial outer membrane permeabilization (MOMP) and cytochrome c (cyt c) release into the cytoplasm, where it stimulates formation of the “apoptosome.” This large, multimeric complex is composed of the adapter protein, apoptotic protease-activating factor-1, and the cysteine protease, caspase-9. Recent studies suggest that proteins involved in the processes leading up to (and including) formation of the apoptosome are subject to various forms of post-translational modification, including proteolysis, phosphorylation,...

/pdf/regulation-of-the-intrinsic-apoptosis-pathway-by-reactive-40hao3dgmo.pdf

Regulation of the Intrinsic Apoptosis Pathway by Reactive Oxygen Species

According to dogma, initiator caspases are activated through proximity-induced homodimerization, but some studies infer that during apoptosis caspase-9 may instead form a holoenzyme with the Apaf-1 apoptosome. Using several biochemical approaches, including a novel site-specific crosslinking technique, we provide the first direct evidence that procaspase-9 homodimerizes within the apoptosome, markedly increasing its avidity for the complex and inducing selective intramolecular cleavage at Asp-315. Remarkably, however, procaspase-9 could also bind via its small subunit to the NOD domain in Apaf-1, resulting in the formation of a heterodimer that more efficiently activated procaspase-3. Following cleavage, the intersubunit linker (and associated conformational changes) in caspase-9-p35/p12 inhibited its ability to form homo- and heterodimers, but feedback cleavage by caspase-3 at Asp-330 removed the linker entirely and partially restored activity to caspase-9-p35/p10. Thus, the apoptosome mediates the formation of caspase-9 homo- and heterodimers, both of which are impacted by cleavage and contribute to its overall function.

/pdf/the-apaf-1-apoptosome-induces-formation-of-caspase-9-homo-306jherag5.pdf

The Apaf-1 apoptosome induces formation of caspase-9 homo- and heterodimers with distinct activities.

For nearly 2 decades, investigators have debated whether cysteinyl-aspartate-specific protease 9 (caspase-9) is activated within the apoptotic protease-activating factor 1 (Apaf-1) apoptosome through proximity-induced homodimerization or through formation of a holoenzyme. Recently, we have demonstrated that caspase-9 forms (and likely transitions between) both caspase-9 homo- and Apaf-1:caspase-9 heterodimers, each of which plays unique roles in the recruitment and activation of caspase-9.

Caspase-9 swings both ways in the apoptosome.

Purpose: To investigate the effects of ataxia telangiectasia mutated (ATM)-regulated reactive oxygen species (ROS) and cell death pathways on the response of U87MG glioma cells to ionising radiation (IR) and oxidative stress.Material and methods: ATM expression was blocked in U87MG glioma cells using a small interfering RNA (siRNA) technique. Cell survival, sub-lethal damage (SLD), and potential lethal damage (PLD) repair following IR were assessed by clonogenic assay while changes in intracellular ROS, the apoptosis, and autophagy were followed by flow cytometry and Western blotting.Results: Blocking ATM expression in U87MG cells increased intracellular ROS levels and sensitivity to the cytotoxic effects of IR and oxygen stress; effects that could be partly counteracted by the antioxidant N-acetylcysteine (NAC). Knock down of ATM rendered cells unable to repair sub-lethal or potentially lethal damage and DNA double strand breaks (DSB) after IR exposure; something that NAC could not counteract. ATM did co...

Inactivation of ataxia telangiectasia mutated gene can increase intracellular reactive oxygen species levels and alter radiation-induced cell death pathways in human glioma cells

Chu Chiao Wu

Papers

Regulation of the Intrinsic Apoptosis Pathway by Reactive Oxygen Species

The Apaf-1 apoptosome induces formation of caspase-9 homo- and heterodimers with distinct activities.

Caspase-9 swings both ways in the apoptosome.

Inactivation of ataxia telangiectasia mutated gene can increase intracellular reactive oxygen species levels and alter radiation-induced cell death pathways in human glioma cells

DARK apoptosome secrets come to light.