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

Shuhei Hamano1, Tomoe Maruyama1, Midori Suzuki1

  • 1Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.

International Journal of Molecular Sciences
|November 13, 2025
PubMed

Insights

Poly (ADP-ribose) polymerase-1 (PARP-1) mediates parthanatos, a cell death pathway. AMP-activated protein kinase (AMPK) activation limits parthanatos by inhibiting Bim upregulation, revealing a novel regulatory mechanism.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell death
  • Biochemistry

Background:

  • Parthanatos is a regulated cell death (RCD) pathway involving poly (ADP-ribose) polymerase-1 (PARP-1).
  • The precise mechanisms and physiological roles of parthanatos remain largely unelucidated.
  • Understanding RCD pathways is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying parthanatos.
  • To explore the role of AMP-activated protein kinase (AMPK) in regulating parthanatos.
  • To elucidate the relationship between PARP-1, AMPK, and Bcl-2 family proteins in cell death.

Main Methods:

  • Biochemical and cellular experiments were performed on human fibrosarcoma HT1080 cells.
  • Investigated parthanatos induction by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG).
  • Assessed the involvement of BAX/BAK and Bcl-2-interacting mediator of cell death (Bim) in parthanatos pathways.

Main Results:

  • MNNG-induced parthanatos proceeds via BAX/BAK or Bim-dependent pathways.
  • MNNG activates AMPK through PARP-1-dependent ATP depletion.
  • AMPK selectively downregulates Bim-mediated parthanatos by inhibiting Bim upregulation.

Conclusions:

  • AMPK signaling, activated by PARP-1-dependent ATP depletion, acts as a negative regulator of parthanatos.
  • This study reveals a novel link between AMPK and parthanatos, impacting Bim-mediated cell death.
  • Findings offer insights into the physiological significance of parthanatos and potential therapeutic targets.
Keywords:
AMPKBimparthanatos

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