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Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death

Author

Listed:
  • Christopher P. Baines

    (Children's Hospital Medical Center)

  • Robert A. Kaiser

    (Children's Hospital Medical Center)

  • Nicole H. Purcell

    (Children's Hospital Medical Center)

  • N. Scott Blair

    (Children's Hospital Medical Center)

  • Hanna Osinska

    (Children's Hospital Medical Center)

  • Michael A. Hambleton

    (Children's Hospital Medical Center)

  • Eric W. Brunskill

    (University of Cincinnati, Children's Hospital Medical Center)

  • M. Richard Sayen

    (The Scripps Research Institute)

  • Roberta A. Gottlieb

    (The Scripps Research Institute)

  • Gerald W. Dorn

    (University of Cincinnati, Children's Hospital Medical Center)

  • Jeffrey Robbins

    (Children's Hospital Medical Center)

  • Jeffery D. Molkentin

    (Children's Hospital Medical Center)

Abstract

Mitochondria play a critical role in mediating both apoptotic and necrotic cell death. The mitochondrial permeability transition (mPT) leads to mitochondrial swelling, outer membrane rupture and the release of apoptotic mediators. The mPT pore is thought to consist of the adenine nucleotide translocator, a voltage-dependent anion channel, and cyclophilin D (the Ppif gene product), a prolyl isomerase located within the mitochondrial matrix1,2. Here we generated mice lacking Ppif and mice overexpressing cyclophilin D in the heart. Ppif null mice are protected from ischaemia/reperfusion-induced cell death in vivo, whereas cyclophilin D-overexpressing mice show mitochondrial swelling and spontaneous cell death. Mitochondria isolated from the livers, hearts and brains of Ppif null mice are resistant to mitochondrial swelling and permeability transition in vitro. Moreover, primary hepatocytes and fibroblasts isolated from Ppif null mice are largely protected from Ca2+-overload and oxidative stress-induced cell death. However, Bcl-2 family member-induced cell death does not depend on cyclophilin D, and Ppif null fibroblasts are not protected from staurosporine or tumour-necrosis factor-α-induced death. Thus, cyclophilin D and the mitochondrial permeability transition are required for mediating Ca2+- and oxidative damage-induced cell death, but not Bcl-2 family member-regulated death.

Suggested Citation

  • Christopher P. Baines & Robert A. Kaiser & Nicole H. Purcell & N. Scott Blair & Hanna Osinska & Michael A. Hambleton & Eric W. Brunskill & M. Richard Sayen & Roberta A. Gottlieb & Gerald W. Dorn & Jef, 2005. "Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death," Nature, Nature, vol. 434(7033), pages 658-662, March.
  • Handle: RePEc:nat:nature:v:434:y:2005:i:7033:d:10.1038_nature03434
    DOI: 10.1038/nature03434
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    Cited by:

    1. Cecilia Patitucci & Juan Diego Hernández-Camacho & Elodie Vimont & Sonny Yde & Thomas Cokelaer & Thibault Chaze & Quentin Giai Gianetto & Mariette Matondo & Anastasia Gazi & Ivan Nemazanyy & David A. , 2023. "Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    2. Erminia Donnarumma & Michael Kohlhaas & Elodie Vimont & Etienne Kornobis & Thibault Chaze & Quentin Giai Gianetto & Mariette Matondo & Maryse Moya-Nilges & Christoph Maack & Timothy Wai, 2022. "Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure," Nature Communications, Nature, vol. 13(1), pages 1-24, December.

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