AMPK Limits MNNG-Induced Parthanatos by Inhibiting BH3-Only Protein Bim

Parthanatos represents an alternative form of regulated cell death (RCD) mediated by poly (ADP-ribose) polymerase-1 (PARP-1). However, the underlying mechanisms and physiological significance of parthanatos are poorly understood. In this study, we investigated molecular mechanisms of parthanatos in human fibrosarcoma HT1080 cells using biochemical and cellular experiments, and found that parthanatos induced by the alkylating agent <i>N</i>-methyl-<i>N</i>'-nitro-<i>N</i>-nitrosoguanidine (MNNG) is mediated by two alternative pathways that depend on pro-death Bcl-2 family proteins BAX/BAK or Bcl-2-interacting mediator of cell death (Bim). Moreover, we found that MNNG activates AMP-activated protein kinase (AMPK) through PARP-1-dependent ATP depletion, and then AMPK selectively downregulates MNNG-induced parthanatos mediated by Bim but not BAX/BAK. Under unstimulated conditions, expression levels of Bim were below the detection limit. Interestingly, MNNG strongly upregulated the protein expression levels of Bim, but only when the activation of AMPK was inhibited. These observations suggest that the AMPK signaling pathways activated by PARP-1-dependent ATP depletion limit parthanatos by blocking the Bim upregulation triggering Bim-mediated parthanatos. Thus, our results demonstrate a novel relationship between AMPK and parthanatos, which may provide insights into the physiological roles of parthanatos.