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Cyclophilin D-sensitive mitochondrial permeability transition in adult human brain and liver mitochondria.

Hansson, Magnus LU ; Morota, Saori LU ; Chen, Li; Matsuyama, Nagahisa; Suzuki, Yoshiaki; Nakajima, Satoshi; Tanoue, Tadashi; Omi, Akibumi; Shibasaki, Futoshi and Shimazu, Motohide, et al. (2011) In Journal of Neurotrauma 28. p.143-153
Abstract
The mitochondrial permeability transition (mPT) is considered to be a major cause of cell death under a variety of pathophysiological conditions of the CNS and other organs. Pharmacological inhibition or genetic knock-out of the matrix protein cyclophilin D (CypD) prevents mPT and cell degeneration in several models of brain injury. Provided that findings in animal models can be translatable to human disease, pharmacological inhibition of mPT offers a promising therapeutic target. The objective of this study was to validate the presence of a CypD-sensitive mPT in adult human brain and liver mitochondria. In order to perform functional characterization of human mitochondria, fresh tissue samples were obtained during hemorrhage or tumor... (More)
The mitochondrial permeability transition (mPT) is considered to be a major cause of cell death under a variety of pathophysiological conditions of the CNS and other organs. Pharmacological inhibition or genetic knock-out of the matrix protein cyclophilin D (CypD) prevents mPT and cell degeneration in several models of brain injury. Provided that findings in animal models can be translatable to human disease, pharmacological inhibition of mPT offers a promising therapeutic target. The objective of this study was to validate the presence of a CypD-sensitive mPT in adult human brain and liver mitochondria. In order to perform functional characterization of human mitochondria, fresh tissue samples were obtained during hemorrhage or tumor surgery and mitochondria were rapidly isolated. Mitochondrial calcium retention capacity, a quantitative assay for mPT, was significantly increased by the CypD inhibitor cyclosporin A in both human brain and liver mitochondria, whereas thiol-reactive compounds and oxidants sensitized mitochondria to calcium-induced mPT. Brain mitochondria underwent swelling upon calcium overload, which was reversible upon calcium removal. To further explore mPT of human mitochondria, liver mitochondria were demonstrated to exhibit several classical features of the mPT phenomenon such as calcium-induced loss of membrane potential and respiratory coupling, as well as release of the pro-apoptotic protein cytochrome c. It is concluded that adult viable human brain and liver mitochondria possess an active CypD-sensitive mPT. The present findings support the rationale of CypD and mPT inhibition as pharmacological targets in acute and chronic neurodegeneration. (Less)
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Contribution to journal
publication status
published
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Journal of Neurotrauma
volume
28
pages
143 - 153
publisher
Mary Ann Liebert, Inc.
external identifiers
  • WOS:000286491800014
  • PMID:21121808
  • Scopus:78651358741
ISSN
1557-9042
DOI
10.1089/neu.2010.1613
language
English
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yes
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f85816e4-e941-4cb7-9b89-d2727d9a8808 (old id 1756860)
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http://www.ncbi.nlm.nih.gov/pubmed/21121808?dopt=Abstract
date added to LUP
2011-01-03 11:44:41
date last changed
2016-10-30 04:34:40
@misc{f85816e4-e941-4cb7-9b89-d2727d9a8808,
  abstract     = {The mitochondrial permeability transition (mPT) is considered to be a major cause of cell death under a variety of pathophysiological conditions of the CNS and other organs. Pharmacological inhibition or genetic knock-out of the matrix protein cyclophilin D (CypD) prevents mPT and cell degeneration in several models of brain injury. Provided that findings in animal models can be translatable to human disease, pharmacological inhibition of mPT offers a promising therapeutic target. The objective of this study was to validate the presence of a CypD-sensitive mPT in adult human brain and liver mitochondria. In order to perform functional characterization of human mitochondria, fresh tissue samples were obtained during hemorrhage or tumor surgery and mitochondria were rapidly isolated. Mitochondrial calcium retention capacity, a quantitative assay for mPT, was significantly increased by the CypD inhibitor cyclosporin A in both human brain and liver mitochondria, whereas thiol-reactive compounds and oxidants sensitized mitochondria to calcium-induced mPT. Brain mitochondria underwent swelling upon calcium overload, which was reversible upon calcium removal. To further explore mPT of human mitochondria, liver mitochondria were demonstrated to exhibit several classical features of the mPT phenomenon such as calcium-induced loss of membrane potential and respiratory coupling, as well as release of the pro-apoptotic protein cytochrome c. It is concluded that adult viable human brain and liver mitochondria possess an active CypD-sensitive mPT. The present findings support the rationale of CypD and mPT inhibition as pharmacological targets in acute and chronic neurodegeneration.},
  author       = {Hansson, Magnus and Morota, Saori and Chen, Li and Matsuyama, Nagahisa and Suzuki, Yoshiaki and Nakajima, Satoshi and Tanoue, Tadashi and Omi, Akibumi and Shibasaki, Futoshi and Shimazu, Motohide and Ikeda, Yukio and Uchino, Hiroyuki and Elmer, Eskil},
  issn         = {1557-9042},
  language     = {eng},
  pages        = {143--153},
  publisher    = {ARRAY(0x8ff5398)},
  series       = {Journal of Neurotrauma},
  title        = {Cyclophilin D-sensitive mitochondrial permeability transition in adult human brain and liver mitochondria.},
  url          = {http://dx.doi.org/10.1089/neu.2010.1613},
  volume       = {28},
  year         = {2011},
}