Cell Death by Necrosis, a Regulated Way to Go

Abstract

Apoptosis is a programmed form of cell death with well-defined morphological traits that are often associated with activation of caspases. More recently evidence has become available demonstrating that upon caspase inhibition alternative programs of cell death are executed, including ones with features characteristic of necrosis. These findings have changed our view of necrosis as a passive and essentially accidental form of cell death to that of an active, regulated and controllable process. Also necrosis has now been observed in parallel with, rather than as an alternative pathway to, apoptosis. Thus, cell death responses are extremely flexible despite being programmed. In this review, some of the hallmarks of different programmed cell death modes have been highlighted before focusing the discussion on necrosis. Obligatory events associated with this form of cell death include uncompensated cell swelling and related changes at the plasma membrane. In this context, representatives of the transient receptor channel family and their regulation are discussed. Also mechanisms that lead to execution of the necrotic cell death program are highlighted. Emphasis is laid on summarizing our understanding of events that permit switching between cell death modes and how they connect to necrosis. Finally, potential implications for the treatment of some disease states are mentioned.

The Caveolin-1 Connection to Cell Death and Survival

“…Treatment of isolated macrophages activated in vivo in mice with apoptosis-inducing agents lead to a dramatic increase in Caveolin-1 levels while Caveolin-2 is not affected. Phosphatidylserine (PS) externalization is considered a defining feature associated with apoptosis [111]. Interestingly, Caveolin-1 is present in lipid rafts and colocalizes with PS at the cell surface of apoptotic macrophages, where it is suggested to be involved in the efficient externalization of PS [112].…”

Cardiac reanimation: targeting cardiomyocyte death by BNIP3 and NIX/BNIP3L

“…These organelles are the predominant sites for intracellular calcium stores, and the highly organized subcellular architecture of adult cardiac myocytes enforces close proximity between SR and mitochondria, making it possible for calcium to transfer from SR to mitochondria through junctional microdomains referred to as 'calcium hot-spots' (Rizzuto and Pozzan, 2006). Calcium delivery to mitochondria and uptake by the calcium uniporter are a potent stimulus for mitochondrial permeability transition (MPT) in the heart and elsewhere, and the resulting inner and outer membrane rupture leads to cell death from ATP depletion, called 'programmed necrosis' (Nakayama et al, 2007;Henriquez et al, 2008). The Dorn group found that there is a direct relationship between NIX/BNIP3L level in NIX/BNIP3L-overexpressing and -knockout mice and SR calcium content, suggesting that ER/SRlocalized NIX/BNIP3L can affect intracellular calcium stores in a similar manner as previously reported for BCL2 and BAX (Foyouzi-Youssefi et al, 2000;Nutt et al, 2002;Scorrano et al, 2003).…”

Apoptosis and necrosis mediate skeletal muscle fiber loss in age‐induced mitochondrial enzymatic abnormalities

“…Prominent features of necrosis are ATP depletion, loss of ion homeostasis and membrane polarity leading to rapid swelling of the cell, membrane rupture, and subsequent release of cellular contents. Necrosis is neither organized nor executed in a similar manner to apoptosis, and cell death is a consequence of irreparable damage (Henriquez et al ., 2008). Necrosis therefore frequently occurs during pathological conditions including stroke, ischemia, and neurodegenerative disorders (Syntichaki et al ., 2002; Malhi et al ., 2006; Henriquez et al ., 2008).…”

“…Necrosis is neither organized nor executed in a similar manner to apoptosis, and cell death is a consequence of irreparable damage (Henriquez et al ., 2008). Necrosis therefore frequently occurs during pathological conditions including stroke, ischemia, and neurodegenerative disorders (Syntichaki et al ., 2002; Malhi et al ., 2006; Henriquez et al ., 2008). Inflammation is associated with necrosis and not with apoptotic cell death (Scaffidi et al ., 2002).…”