Alternative Cell Death Pathways and Cell Metabolism

While necroptosis has for long been viewed as an accidental mode of cell death triggered by physical or chemical damage, it has become clear over the last years that necroptosis can also represent a programmed form of cell death in mammalian cells. Key discoveries in the field of cell death research, including the identification of critical components of the necroptotic machinery, led to a revised concept of cell death signaling programs. Several regulatory check and balances are in place in order to ensure that necroptosis is tightly controlled according to environmental cues and cellular needs. This network of regulatory mechanisms includes metabolic pathways, especially those linked to mitochondrial signaling events. A better understanding of these signal transduction mechanisms will likely contribute to open new avenues to exploit our knowledge on the regulation of necroptosis signaling for therapeutic application in the treatment of human diseases. 1. Introduction There are several forms of cell death in mammalian cells, among them apoptosis and necrosis as the two best characterized and most intensively studied modes of cell death [1]. Apoptosis is characterized by a series of programmed events, including membrane blebbing, caspase activation, and internucleosomal DNA fragmentation [1]. In contrast to apoptosis, necrosis represents a form of cell death that typically lacks the activation of caspases, while it involves swelling of mitochondria, irreversible damage to cellular membranes, eventually leading to spilling of the intracellular content into the surrounding environment [1]. In addition, a regulated form of necrosis, that is, necroptosis, has recently been identified that proceeds in a programmed and controlled manner [2]. Necroptosis refers to RIP1- and/or RIP3-dependent regulated necrosis [1]. A better understanding of the molecular mechanisms that regulate necroptosis signal transduction may open new perspectives for targeted modulation and therapeutic exploitation of necroptosis signaling. This paper will focus on the crosstalk between necroptosis and metabolic signaling events, in particular redox signaling. 2. Necroptosis Signaling There are various stimuli that can engage necroptosis, including ligands of the death receptor family such as TNFα, chemical or physical damage, or hypoxic conditions [2]. Since necroptosis represents a programmed form of cell death, there are clearly delineated signal transduction cascades that eventually lead to the demise of the cell. For example, in TNFα-triggered necroptosis, binding of the death