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Farnesyl pyrophosphate is a new danger signal inducing acute cell death

Jing Chen1, Xiaochen Zhang2, Liping Li3

  • 1School of Life Sciences, Institute for Immunology, Ministry of Education Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China.

Plos Biology
|April 26, 2021
PubMed

Insights

Farnesyl pyrophosphate (FPP), a mevalonate pathway metabolite, acts as a novel danger signal triggering acute cell death. This FPP-TRPM2 axis contributes to neuron loss in stroke and ischemic injury.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Cell Biology

Background:

  • Lytic cell death releases danger signals, promoting inflammation and tissue damage.
  • The mevalonate (MVA) pathway is a critical metabolic process.
  • Understanding novel danger signals is crucial for treating conditions like stroke.

Purpose of the Study:

  • To identify new danger signals involved in lytic cell death.
  • To investigate the role of mevalonate pathway intermediates in cell death.
  • To elucidate the mechanism of FPP-induced cell death and its relevance in ischemic stroke.

Main Methods:

  • Metabolic analysis to identify FPP accumulation.
  • Cell death assays to assess FPP's cytotoxic effects.
  • Electrophysiology and calcium imaging to study FPP-TRPM2 interactions.
  • Middle cerebral artery occlusion (MCAO) mouse model for in vivo validation.

Main Results:

  • Farnesyl pyrophosphate (FPP), an MVA pathway intermediate, functions as a novel danger signal.
  • Extracellular calcium influx and TRPM2 channel activation are essential for FPP-induced cell death.
  • FPP directly activates TRPM2, leading to ion influx and cell death, independent of downstream MVA pathways.
  • FPP accumulates in the brain during MCAO, implicating the FPP-TRPM2 axis in ischemic injury.

Conclusions:

  • Farnesyl pyrophosphate (FPP) is a newly discovered danger signal mediating acute cell death.
  • The FPP-TRPM2-calcium influx pathway is a critical mechanism in ischemic stroke-induced neuron loss.
  • Targeting the FPP-TRPM2 axis may offer therapeutic strategies for stroke and other ischemic injuries.

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