More than one way to die: apoptosis, necrosis and reactive oxygen damage

Abstract

Cell death is an essential phenomenon in normal development and homeostasis, but also plays a crucial role in various pathologies. Our understanding of the molecular mechanisms involved has increased exponentially, although it is still far from complete. The morphological features of a cell dying either by apoptosis or by necrosis are remarkably conserved for quite different cell types derived from lower or higher organisms. At the molecular level, several gene products play a similar, crucial role in a major cell death pathway in a worm and in man. However, one should not oversimplify. It is now evident that there are multiple pathways leading to cell death, and some cells may have the required components for one pathway, but not for another, or contain endogenous inhibitors which preclude a particular pathway. Furthermore, different pathways can co-exist in the same cell and are switched on by specific stimuli. Apoptotic cell death, reported to be non-inflammatory, and necrotic cell death, which may be inflammatory, are two extremes, while the real situation is usually more complex. We here review the distinguishing features of the various cell death pathways: caspases (cysteine proteases cleaving after particular aspartate residues), mitochondria and/or reactive oxygen species are often, but not always, key components. As these various caspase-dependent and caspase-independent cell death pathways are becoming better characterized, we may learn to differentiate them, fill in the many gaps in our understanding, and perhaps exploit the knowledge acquired for clinical benefit.

Oxidative Stress and Skin Cancer: An Overview

“…Skin contains antioxidant defenses, which nullify ROS including free radicals, but these defenses will be overwhelmed if the dose of UV light is high enough, and this result in free radical damage to cellular components such as proteins, lipids and DNA [7,8]. ROS induced by oxidative stress can ultimately lead to apoptotic or necrotic cell death [9]. Especially, the accumulated ROS plays a critical role in the intrinsic aging and photo-aging of human skin in vivo, thus suggested to be responsible for various skin cancers and other cutaneous inflammatory disorders [10,11].…”

Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

“…Both T-cell activation and apoptosis require the energy provided by ATP [46]. Intracellular ATP concentration is a key switch in the decision of the cell to die by apoptosis or necrosis [26] and, therefore, depletion of ATP might be responsible for defective H 2 O 2 -induced apoptosis and a shift to necrosis in patients with SLE.…”

Cell death, proliferation and repair in human myocarditis responding to immunosuppressive therapy

“…On follow-up biopsies of responders cell death decreased consistently, specifically by 68% for cell necrosis and 86% for cell apoptosis, allowing cell repair and proliferation to become effective biological events for the improvement of cardiac function. Several mechanisms may have concurred to cell rescue including: (a) removal of natural killer cells and activated T-lymphocytes that with their perforins and granzymes produce damage of myocyte membrane inducing cell necrosis and DNA fragmentation leading to apoptosis; 16,17 (b) Inhibition of cytokine and free radical production (particularly TNF-a and IL-1) that can activate intracellular caspase cascade and ultimately myocyte apoptosis; 18 (c) reduction of reactive oxygen species production (including NO), that at high levels can induce necrosis while at lower levels can trigger apoptosis; 19 (d) reduction of left ventricular load due to the improvement of cardiac dimensions and contractility. 20 It is noteworthy that even severe degrees of cell death can be remarkably slowed or stopped if the treatment is really able to interfere with the underlying mechanism of damage.…”