Necroptosis, a novel form of caspase‐independent cell death, contributes to neuronal damage in a retinal ischemia‐reperfusion injury model

Rosenbaum, Daniel M.; Degterev, Alexei; David, Joel; Rosenbaum, Pearl S.; Roth, Steven; Grotta, James C.; Cuny, Gregory D.; Yuan, Junying; Savitz, Sean I

doi:10.1002/jnr.22314

Cited by 222 publications

(153 citation statements)

References 74 publications

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“…Finally, to demonstrate the in vivo relevance of these findings, cambinol was assayed in a model of renal ischemiareperfusion injury (IRI). Necroptosis is indeed thought to have a major pathological role during renal ischemia-reperfusion, based on the organ-preserving properties of necrostatin-1 in animal models 44,45 and the relative resistance of RIPK3-KO animals to IRI. 46 IRI was induced by clamping of left renal artery for 20 min followed by 24 h of reperfusion.…”

Section: Intracellular Nadmentioning

confidence: 99%

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

et al. 2015

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Cellular necrosis has long been regarded as an incidental and uncontrolled form of cell death. However, a regulated form of cell death termed necroptosis has been identified recently. Necroptosis can be induced by extracellular cytokines, pathogens and several pharmacological compounds, which share the property of triggering the formation of a RIPK3-containing molecular complex supporting cell death. Of interest, most ligands known to induce necroptosis (including notably TNF and FASL) can also promote apoptosis, and the mechanisms regulating the decision of cells to commit to one form of cell death or the other are still poorly defined. We demonstrate herein that intracellular nicotinamide adenine dinucleotide (NAD + ) has an important role in supporting cell progression to necroptosis. Using a panel of pharmacological and genetic approaches, we show that intracellular NAD + promotes necroptosis of the L929 cell line in response to TNF. Use of a pan-sirtuin inhibitor and shRNA-mediated protein knockdown led us to uncover a role for the NAD + -dependent family of sirtuins, and in particular for SIRT2 and SIRT5, in the regulation of the necroptotic cell death program. Thus, and in contrast to a generally held view, intracellular NAD + does not represent a universal pro-survival factor, but rather acts as a key metabolite regulating the choice of cell demise in response to both intrinsic and extrinsic factors. + as a substrate in a number of regulatory processes has shed a new light on its role in cell physiology. Indeed, NAD + represents a substrate for a wide range of enzymes including cADP-ribose synthases, poly (ADP-ribose) polymerases (PARPs) and the sirtuin family of NAD + -dependent deacylases (SIRTs). In marked contrast to its role in energy metabolism, the involvement of NAD + in these enzymatic reactions is based on its ability to function as a donor of ADP-ribose, a reaction that, if sustained, can lead to the depletion of the intracellular NAD + pool. 1-5The pro-survival role of NAD + has been particularly well described in cells exposed to genotoxic/oxidative stress. In response to DNA damage, PARP1, the founding and most abundant member of the PARP family, binds to DNA strand breaks and initiates a repair response by catalyzing the posttranslational modification of several nuclear proteins, including itself. This protective response is characterized by the transfer of successive units of the ADP-ribose moiety (up to 200 units) from NAD + to other proteins, compromising therefore both energy production (slowing the rate of glycolysis, electron transport and ATP formation) and activity of other NAD + -dependent enzymes through NAD + depletion. 6,7 Moreover, PARP1-synthesized PAR polymers can be degraded into free oligomers, known to translocate to the mitochondria where they can trigger the release of AIF from mitochondria to the nucleus. [8][9][10][11] The precise molecular steps linking PARP1 activation to this form of stress-induced cell death, termed parthanatos, have not been fully elucidated, and...

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Section: Intracellular Nadmentioning

confidence: 99%

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

et al. 2015

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“…More recently, new forms of necroptosis have been unveiled (67)(68)(69)(70)(71). One of them is the pathway scrutinized in our laboratory: alkylating DNA damage (MNNG)-mediated PCD (11,33,39,51).…”

Section: Aif-mediated Caspase-independent Necroptosismentioning

confidence: 99%

AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics

et al. 2011

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SummaryCell death has been initially divided into apoptosis, in which the cell plays an active role, and necrosis, which is considered a passive cell death program. Intense research performed in the last decades has concluded that ''programmed'' cell death (PCD) is a more complex physiological process than initially thought. Indeed, although in most cases the PCD process is achieved via a family of Cys proteases known as caspases, an important number of regulated PCD pathways do not involve this family of proteases. As a consequence, active forms of PCD are initially referred to as caspase-dependent and caspase-independent. More recent data has revealed that there are also active caspase-independent necrotic pathways defined as necroptosis (programmed necrosis). The existence of necroptotic forms of death was corroborated by the discovery of key executioners such as the kinase RIP1 or the mitochondrial protein apoptosis-inducing factor (AIF). AIF is a Janus protein with a redox activity in the mitochondria and a pro-apoptotic function in the nucleus. We have recently described a particular form of AIF-mediated caspase-independent necroptosis that also implicates other molecules such as PARP-1, calpains, Bax, Bcl-2, histone H2AX, and cyclophilin A. From a therapeutic point of view, the unraveling of this new form of PCD poses a question: is it possible to modulate this necroptotic pathway independently of the classical apoptotic paths? Because the answer is yes, a wider understanding of AIF-mediated necroptosis could theoretically pave the way for the development of new drugs that modulate PCD. To this end, we present here an overview of the current knowledge of AIF and AIF-mediated necroptosis. We also summarize the state of the art in some of the most interesting therapeutic strategies that could target AIF or the AIF-mediated necroptotic pathway.

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“…8 And in some but not all situations, necroptosis is also characterized by activation of autophagy, which in turn contributes to cell death. [9][10][11][12] No matter whether autophagy is involved or not, reactive oxygen species (ROS) and the death domain-containing kinase RIP1 contribute to this alternative form of cell death. disruption of the plasma membrane (Fig.…”

Section: Zvad-induced Autophagic Cell Death Requires C-src-dependent mentioning

confidence: 99%

zVAD-induced autophagic cell death requires c-Src-dependent ERK and JNK activation and reactive oxygen species generation

Chen

Chiu

Maa³

et al. 2011

Autophagy

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Necroptosis, a novel form of caspase‐independent cell death, contributes to neuronal damage in a retinal ischemia‐reperfusion injury model

Abstract: Necroptosis is an important mode of neuronal cell death and involves autophagy in a model of retinal ischemia.

Cited by 222 publications

References 74 publications

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics

zVAD-induced autophagic cell death requires c-Src-dependent ERK and JNK activation and reactive oxygen species generation

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