The paradigmatic notion of apoptosis as a non-cell autonomous inert process has been challenged since the original discovery that dying cells can produce and release ‘find-me’ signals that account for phagocytes recruitment, corpse engulfment and tissue remodeling in distinct physiological contexts [1]. In the time frame spanning from the initiation of the apoptotic cascade to immune clearance, it remains unclear how dying cells influence neighboring cells in a tissue.

In a recent Nature paper, Ravichandran and collaborators hypothesize that apoptotic cells may coordinate pathophysiologically relevant stress responses by communicating their demise to neighboring live cells through their metabolic secretome [2]. The authors used different cellular models (Jurkat T cells, bone marrow derived macrophages, and primary mouse thymocytes) exposed to different apoptotic cues, in experimental settings in which 80% of the cells became apoptotic (yet maintained plasma membrane integrity). In these models, the authors performed an untargeted mass spectrometric metabolomics analysis of the intracellular versus extracellular metabolomes. Five metabolites (adenosine monophosphate, guanosine 5′-monophosphate, creatine, spermidine, and glycerol-3-phosphate) were found to be differentially enriched in the supernatant of apoptotic cells, irrespective of the cell line tested. A sixth extracellular metabolite, adenosine triphosphate (previously known as a chemotactic factor for inflammatory immune cells recruitment) [3] was found commonly upregulated after luciferase-based assessment. Importantly, the secretion of these metabolites was significantly attenuated by pre-treatment of cells with the pan-caspase inhibitor Z-VAD-fmk [4], reinforcing the idea that the apoptotic process is associated to the active release of biologically meaningful metabolites [2].

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