Genetic approach to elucidate the role of cyclophilin d in traumatic brain injury pathology

Ryan D. Readnower, William Brad Hubbard, Olivia J. Kalimon, James W. Geddes, Patrick G. Sullivan

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Cyclophilin D (CypD) has been shown to play a critical role in mitochondrial permeability transition pore (mPTP) opening and the subsequent cell death cascade. Studies consistently demon-strate that mitochondrial dysfunction, including mitochondrial calcium overload and mPTP opening, is essential to the pathobiology of cell death after a traumatic brain injury (TBI). CypD inhibitors, such as cyclosporin A (CsA) or NIM811, administered following TBI, are neuroprotective and quell neurological deficits. However, some pharmacological inhibitors of CypD have multiple biological targets and, as such, do not directly implicate a role for CypD in arbitrating cell death after TBI. Here, we reviewed the current understanding of the role CypD plays in TBI pathobiology. Further, we directly assessed the role of CypD in mediating cell death following TBI by utilizing mice lacking the CypD encoding gene Ppif. Following controlled cortical impact (CCI), the genetic knockout of CypD protected acute mitochondrial bioenergetics at 6 h post-injury and reduced subacute cortical tissue and hippocampal cell loss at 18 d post-injury. The administration of CsA following experimental TBI in Ppif-/-mice improved cortical tissue sparing, highlighting the multiple cellular targets of CsA in the mitigation of TBI pathology. The loss of CypD appeared to desensitize the mitochondrial response to calcium burden induced by TBI; this maintenance of mitochondrial function underlies the observed neuroprotective effect of the CypD knockout. These studies highlight the importance of maintaining mitochondrial homeostasis after injury and validate CypD as a therapeutic target for TBI. Further, these results solidify the beneficial effects of CsA treatment following TBI.

Original languageEnglish
Article number199
Pages (from-to)1-15
Number of pages15
JournalCells
Volume10
Issue number2
DOIs
StatePublished - Feb 1 2021

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Controlled cortical impact
  • Cyclosporin a
  • Mitochondria
  • Mitochondrial bioenergetics
  • Mitochondrial permeability transition
  • NIM811
  • Neuroprotection
  • Ppif

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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