Complex contribution of cyclophilin D to Ca2+-induced permeability transition in brain mitochondria, with relation to the bioenergetic state

Judit Doczi, Lilla Turiák, Szilvia Vajda, Miklós Mándi, B. Törőcsik, Akos A. Gerencser, Gergely Kiss, Csaba Konràd, V. Ádám-Vizi, C. Chinopoulos

Research output: Contribution to journalArticle

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Abstract

Cyclophilin D (cypD)-deficient mice exhibit resistance to focal cerebral ischemia and to necrotic but not apoptotic stimuli. To address this disparity, we investigated isolated brain and in situ neuronal and astrocytic mitochondria from cypD-deficient and wild-type mice. Isolated mitochondria were challenged by high Ca2+, and the effects of substrates and respiratory chain inhibitors were evaluated on permeability transition pore opening by light scatter. In situ neuronal and astrocytic mitochondria were visualized by mito-DsRed2 targeting and challenged by calcimycin, and the effects of glucose, NaCN, and an uncoupler were evaluated by measuring mitochondrial volume. In isolated mitochondria, Ca2+ caused a large cypD-dependent change in light scatter in the absence of substrates that was insensitive to Ruthenium red or Ru360. Uniporter inhibitors only partially affected the entry of free Ca2+ in the matrix. Inhibition of complex III/IV negated the effect of substrates, but inhibition of complex I was protective. Mitochondria within neurons and astrocytes exhibited cypD-independent swelling that was dramatically hastened when NaCN and 2-deoxyglucose were present in a glucose-free medium during calcimycin treatment. In the presence of an uncoupler, cypD-deficient astrocytic mitochondria performed better than wild-type mitochondria, whereas the opposite was observed in neurons. Neuronal mitochondria were examined further during glutamate-induced delayed Ca2+ deregulation. CypD-knock-out mitochondria exhibited an absence or a delay in the onset of mitochondrial swelling after glutamate application. Apparently, some conditions involving deenergization render cypD an important modulator of PTP in the brain. These findings could explain why absence of cypD protects against necrotic (deenergized mitochondria), but not apoptotic (energized mitochondria) stimuli.

Original languageEnglish
Pages (from-to)6345-6353
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number8
DOIs
Publication statusPublished - Feb 25 2011

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Mitochondria
Energy Metabolism
Permeability
Brain
Calcimycin
Neurons
Swelling
Glutamic Acid
cyclophilin D
Substrates
Mitochondrial Swelling
Mitochondrial Size
Light
Glucose
Ruthenium Red
Deregulation
Electron Transport Complex III
Deoxyglucose
Electron Transport
Brain Ischemia

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Complex contribution of cyclophilin D to Ca2+-induced permeability transition in brain mitochondria, with relation to the bioenergetic state. / Doczi, Judit; Turiák, Lilla; Vajda, Szilvia; Mándi, Miklós; Törőcsik, B.; Gerencser, Akos A.; Kiss, Gergely; Konràd, Csaba; Ádám-Vizi, V.; Chinopoulos, C.

In: Journal of Biological Chemistry, Vol. 286, No. 8, 25.02.2011, p. 6345-6353.

Research output: Contribution to journalArticle

Doczi, Judit ; Turiák, Lilla ; Vajda, Szilvia ; Mándi, Miklós ; Törőcsik, B. ; Gerencser, Akos A. ; Kiss, Gergely ; Konràd, Csaba ; Ádám-Vizi, V. ; Chinopoulos, C. / Complex contribution of cyclophilin D to Ca2+-induced permeability transition in brain mitochondria, with relation to the bioenergetic state. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 8. pp. 6345-6353.
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AU - Gerencser, Akos A.

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