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Related Experiment Videos

The permeability transition pore complex: another view.

Andrew P Halestrap1, Gavin P McStay, Samantha J Clarke

  • 1Department of Biochemistry, University of Bristol, Bristol BS8 1TD, UK. A.Halestrap@Bristol.ac.uk

Biochimie
|May 23, 2002
PubMed
Summary

The mitochondrial permeability transition pore (MPTP) regulates cell death by opening in the inner mitochondrial membrane. Cyclophilin D (CyP-D) and adenine nucleotide translocase (ANT) are key components, with cysteine modifications on ANT controlling MPTP activity.

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International journal of molecular sciences·2020

Area of Science:

  • Mitochondrial biology
  • Cell death pathways
  • Biochemistry

Background:

  • Mitochondria are central to initiating apoptosis and necrosis.
  • The mitochondrial permeability transition pore (MPTP) is a key mediator of cell death.
  • MPTP opening is triggered by elevated matrix calcium, oxidative stress, and depleted adenine nucleotides.

Purpose of the Study:

  • To elucidate the molecular composition and regulation of the MPTP.
  • To present a model for MPTP formation involving adenine nucleotide translocase (ANT) and cyclophilin D (CyP-D).
  • To explain the mechanism of action of MPTP modulators.

Main Methods:

  • Analysis of MPTP modulators, including cyclosporin A analogues.
  • Investigating the role of adenine nucleotide translocase (ANT) and cyclophilin D (CyP-D).

Related Experiment Videos

  • Reconstitution studies to determine minimal MPTP components.
  • Examination of cysteine residue modifications on ANT.

    • Main Results:

    • MPTP opening leads to mitochondrial swelling, outer membrane rupture, and apoptosis induction.
    • Cyclosporin A analogues inhibit MPTP by targeting CyP-D.
    • A model proposes MPTP formation via Ca(2+)-triggered ANT conformational change facilitated by CyP-D.
    • Reconstitution studies indicate ANT is a core MPTP component, independent of VDAC.
    • Oxidative cross-linking of ANT cysteines (Cys56, Cys159) regulates MPTP activity.

    Conclusions:

    • The ANT, regulated by CyP-D and Ca(2+), is a central component of the MPTP.
    • ANT cysteine modifications are critical for MPTP regulation.
    • This model explains diverse MPTP modulator effects and suggests ANT as a therapeutic target.