Developmental shift of cyclophilin D contribution to hypoxic-ischemic brain injury

Xiaoyang Wang, Ylva Carlsson, Emy Basso, Changlian Zhu, Catherine I. Rousset, Andrea Rasola, Bengt R. Johansson, Klas Blomgren, Carina Mallard, Paolo Bernardi, Michael A. Forte, Henrik Hagberg

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

Cyclophilin D (CypD), a regulator of the mitochondrial membrane permeability transition pore (PTP), enhances Ca 2+-induced mitochondrial permeabilization and cell death in the brain. However, the role of CypD in hypoxic-ischemic (HI) brain injury at different developmental ages is unknown. At postnatal day (P) 9 or P60, littermates of CypD-deficient [knock-out (KO)], wild-type (WT), and heterozygous mice were subjected to HI, and brain injury was evaluated 7 d after HI. CypD deficiency resulted in a significant reduction of HI brain injury at P60 but worsened injury at P9. After HI, caspase-dependent and-independent cell death pathways were more induced in P9 CypD KO mice than in WT controls, and apoptotic activation was minimal at P60. The PTP had a considerably higher induction threshold and lower sensitivity to cyclosporin A in neonatal versus adult mice. On the contrary, Bax inhibition markedly reduced caspase activation and brain injury in immature mice but was ineffective in the adult brain. Our findings suggest that CypD/PTP is critical for the development of brain injury in the adult, whereas Bax-dependent mechanisms prevail in the immature brain. The role of CypD in HI shifts from a predominantly prosurvival protein in the immature to a cell death mediator in the adult brain.

Original languageEnglish (US)
Pages (from-to)2588-2596
Number of pages9
JournalJournal of Neuroscience
Volume29
Issue number8
DOIs
StatePublished - Feb 25 2009

Keywords

  • Brain injury
  • Cell death
  • Cyclophilin D
  • Development
  • Hypoxia-ischemia
  • Mitochondria

ASJC Scopus subject areas

  • Neuroscience(all)

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    Wang, X., Carlsson, Y., Basso, E., Zhu, C., Rousset, C. I., Rasola, A., Johansson, B. R., Blomgren, K., Mallard, C., Bernardi, P., Forte, M. A., & Hagberg, H. (2009). Developmental shift of cyclophilin D contribution to hypoxic-ischemic brain injury. Journal of Neuroscience, 29(8), 2588-2596. https://doi.org/10.1523/JNEUROSCI.5832-08.2009