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Multi-parameter Measurement of the Permeability Transition Pore Opening in Isolated Mouse Heart Mitochondria
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Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition

Wanfeng Xu1, Yuan Che1, Quan Zhang1

  • 1State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing, China.

Cell Metabolism
|December 14, 2020
PubMed

Insights

Mitochondrial permeability transition activates caspase-4 via the Apaf-1 pyroptosome, leading to GSDME-mediated pyroptosis. This pathway is crucial for cholestatic liver failure and intrinsic pyroptosis under sterile conditions.

Area of Science:

  • Cellular Biology
  • Immunology
  • Pathology

Background:

  • Caspase-4 senses cytosolic bacterial lipopolysaccharide (LPS) and triggers pyroptosis.
  • Mechanisms of caspase-4 activation by host-derived factors remain unclear.

Purpose of the Study:

  • To investigate how caspase-4 is activated by host-derived factors.
  • To elucidate the role of mitochondrial permeability transition (MPT) in caspase-4 activation and pyroptosis.

Main Methods:

  • Induction of MPT using bile acids, calcium overload, or ANT1 activator.
  • Analysis of protein complex assembly (Apaf-1 pyroptosome) involving Apaf-1 and caspase-4.
  • Assessment of caspase-4's downstream cleavage targets, including caspase-3, GSDME, and GSDMD.

Main Results:

  • MPT triggers the assembly of the Apaf-1 pyroptosome (7:2 ratio of Apaf-1 to caspase-4).
  • Activated caspase-4 in the Apaf-1 pyroptosome cleaves caspase-3, leading to GSDME-mediated pyroptosis.
  • Caspase-4-initiated, GSDME-executed pyroptosis is implicated in cholestatic liver failure.

Conclusions:

  • The Apaf-1 pyroptosome is a key machinery for sensing MPT signals and executing pyroptosis.
  • This pathway explains intrinsic pyroptosis under sterile conditions.
  • Findings provide insights into cholestatic liver failure mechanisms.
Keywords:
Apaf-1Caspase-4bile acidgasdermin Emitochondrial permeability transitionpyroptosis

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