Advanced

Calcium-induced mitochondrial permeability transition in CNS-derived mitochondria - Pharmacological aspects of specificity and toxicity in neuroprotection

Månsson, Roland LU (2010) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2010:11.
Abstract
Mitochondria are the main site for energy conversion in the cell. Under certain circumstances, such as excess calcium retention or production of reactive oxygen species, a pore forms at contact sites between the outer and the normally impermeable inner mitochondrial membrane. The ensuing osmotic mitochondrial swelling and loss of bioenergetic function is referred to as the mitochondrial permeability transition (mPT). Certain drugs of the cyclosporine family, such as cyclosporin A (CsA), are reversible inhibitors of mPT via direct interaction with cyclophilin D, which is a known part of the pore forming complex. The limited blood-brain barrier penetration by these drugs has instigated a search for mPT modulating effects among already... (More)
Mitochondria are the main site for energy conversion in the cell. Under certain circumstances, such as excess calcium retention or production of reactive oxygen species, a pore forms at contact sites between the outer and the normally impermeable inner mitochondrial membrane. The ensuing osmotic mitochondrial swelling and loss of bioenergetic function is referred to as the mitochondrial permeability transition (mPT). Certain drugs of the cyclosporine family, such as cyclosporin A (CsA), are reversible inhibitors of mPT via direct interaction with cyclophilin D, which is a known part of the pore forming complex. The limited blood-brain barrier penetration by these drugs has instigated a search for mPT modulating effects among already clinically available compounds with better access to the central nervous system.

In the present study we show that the choice of methods used to evaluate swelling in vitro of mitochondria derived from the CNS could lead to an underestimation of the ability of brain mitochondria to undergo mPT.

We have also re-evaluated minocycline, a semisynthetic antibiotic, which has been reported as a direct mPT inhibitor and found that the previously stated mitochondrial effects (depolarization of the mitochondrial membrane potential and inhibition of calcium-induced swelling) are likely secondary or related to mitochondrial toxicity.

In a successive evaluation of 12 putative mPT inhibiting compounds, none displayed effects comparable to cyclophilin D inhibition by the non-immunosuppressive cyclophilin inhibitor D-MeAla3-EtVal4-Cyclosporin (Debio 025). Mitochondrial effects were often related to a compromised mitochondrial respiratory capacity. Drugs that uncouple or inhibit mitochondrial respiration will decrease mitochondrial calcium uptake but simultaneously reduce calcium retention capacity (CRC) and thus sensitize mitochondria towards mPT. In addition, a compromised respiratory function will impede ATP generation of mitochondria.

It is concluded that screening for putative inhibitors of mPT in complex disease models (such as cellular systems or in vivo models) is extremely prone to confounding influence, the most important being uncoupling and respiratory inhibition. It is suggested that the minimal requirement for a direct mPT inhibitor should include evidence for a specific mitochondrial target and an increased mitochondrial CRC at concentrations that can be translated to safe clinical use. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Andersen, Peter M., Institutionen för farmakologi och klinisk neurovetenskap, Umeå Universitet
organization
publishing date
type
Thesis
publication status
published
subject
keywords
cyclosporin A, mitochondria, brain, calcium, respiration, cell death, permeability transition, calcium retention, minocycline, neuroprotection, Debio 025
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2010:11
pages
140 pages
publisher
Experimental Brain Research, Lund University
defense location
Belfragesalen, Biomedicinskt Centrum, Lund
defense date
2010-04-24 09:30
ISSN
1652-8220
ISBN
978-91-86443-25-2
language
English
LU publication?
yes
id
6c40d3f0-33d8-4048-bbe7-011945c63a3d (old id 1580728)
date added to LUP
2010-03-31 09:50:55
date last changed
2018-05-29 10:00:22
@phdthesis{6c40d3f0-33d8-4048-bbe7-011945c63a3d,
  abstract     = {Mitochondria are the main site for energy conversion in the cell. Under certain circumstances, such as excess calcium retention or production of reactive oxygen species, a pore forms at contact sites between the outer and the normally impermeable inner mitochondrial membrane. The ensuing osmotic mitochondrial swelling and loss of bioenergetic function is referred to as the mitochondrial permeability transition (mPT). Certain drugs of the cyclosporine family, such as cyclosporin A (CsA), are reversible inhibitors of mPT via direct interaction with cyclophilin D, which is a known part of the pore forming complex. The limited blood-brain barrier penetration by these drugs has instigated a search for mPT modulating effects among already clinically available compounds with better access to the central nervous system. <br/><br>
In the present study we show that the choice of methods used to evaluate swelling in vitro of mitochondria derived from the CNS could lead to an underestimation of the ability of brain mitochondria to undergo mPT. <br/><br>
We have also re-evaluated minocycline, a semisynthetic antibiotic, which has been reported as a direct mPT inhibitor and found that the previously stated mitochondrial effects (depolarization of the mitochondrial membrane potential and inhibition of calcium-induced swelling) are likely secondary or related to mitochondrial toxicity. <br/><br>
In a successive evaluation of 12 putative mPT inhibiting compounds, none displayed effects comparable to cyclophilin D inhibition by the non-immunosuppressive cyclophilin inhibitor D-MeAla3-EtVal4-Cyclosporin (Debio 025). Mitochondrial effects were often related to a compromised mitochondrial respiratory capacity. Drugs that uncouple or inhibit mitochondrial respiration will decrease mitochondrial calcium uptake but simultaneously reduce calcium retention capacity (CRC) and thus sensitize mitochondria towards mPT. In addition, a compromised respiratory function will impede ATP generation of mitochondria.<br/><br>
It is concluded that screening for putative inhibitors of mPT in complex disease models (such as cellular systems or in vivo models) is extremely prone to confounding influence, the most important being uncoupling and respiratory inhibition. It is suggested that the minimal requirement for a direct mPT inhibitor should include evidence for a specific mitochondrial target and an increased mitochondrial CRC at concentrations that can be translated to safe clinical use.},
  author       = {Månsson, Roland},
  isbn         = {978-91-86443-25-2},
  issn         = {1652-8220},
  keyword      = {cyclosporin A,mitochondria,brain,calcium,respiration,cell death,permeability transition,calcium retention,minocycline,neuroprotection,Debio 025},
  language     = {eng},
  pages        = {140},
  publisher    = {Experimental Brain Research, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Calcium-induced mitochondrial permeability transition in CNS-derived mitochondria - Pharmacological aspects of specificity and toxicity in neuroprotection},
  volume       = {2010:11},
  year         = {2010},
}