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Mechanisms of cell death are critical in any pathophysiology and hence have been extensively investigated in a number of different organ systems. Initially, the term ‘programmed cell death’ was exclusively applied to apoptosis, where molecular mediators and signalling pathways involved in the process were relatively well characterised. The other form of cell death, namely necrosis, was considered to be an uncontrolled process, where catastrophic events within the cell resulted in a rupture of the plasma membrane with release of cell contents. However, this paradigm has been rapidly evolving as new pathways and mediators, which control necrotic cell death, are discovered. It is now clear that whenever cells die by necrosis, they do so in an ordered systematic manner, which, not surprisingly, shares some components with the apoptotic pathway. This is especially relevant in the liver, where apoptosis was considered to be the main form of cell death in a large number of contexts. These concepts are now changing based on the identification of specific mediators involved in programmed necrosis in response to a number of insults in the liver. The new study from He et al1 in this issue now identifies mitochondrial phosphoglycerate mutase/protein phosphatase 5 (PGAM5) as another key mediator in physiologically relevant cell death in the liver, …
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