Inhibition of cyclophilin D by cyclosporin A promotes retinal ganglion cell survival by preventing mitochondrial alteration in ischemic injury

Cell Death Dis. 2014 Mar 6;5(3):e1105. doi: 10.1038/cddis.2014.80.

Abstract

Cyclosporin A (CsA) inhibits the opening of the mitochondrial permeability transition pore (MPTP) by interacting with cyclophilin D (CypD) and ameliorates neuronal cell death in the central nervous system against ischemic injury. However, the molecular mechanisms underlying CypD/MPTP opening-mediated cell death in ischemic retinal injury induced by acute intraocular pressure (IOP) elevation remain unknown. We observed the first direct evidence that acute IOP elevation significantly upregulated CypD protein expression in ischemic retina at 12 h. However, CsA prevented the upregulation of CypD protein expression and promoted retinal ganglion cell (RGC) survival against ischemic injury. Moreover, CsA blocked apoptotic cell death by decreasing cleaved caspase-3 protein expression in ischemic retina. Of interest, although the expression level of Bcl-xL protein did not show a significant change in ischemic retina treated with vehicle or CsA at 12 h, ischemic damage induced the reduction of Bcl-xL immunoreactivity in RGCs. More importantly, CsA preserved Bcl-xL immunoreactivity in RGCs of ischemic retina. In parallel, acute IOP elevation significantly increased phosphorylated Bad (pBad) at Ser112 protein expression in ischemic retina at 12 h. However, CsA significantly preserved pBad protein expression in ischemic retina. Finally, acute IOP elevation significantly increased mitochondrial transcription factor A (Tfam) protein expression in ischemic retina at 12 h. However, CsA significantly preserved Tfam protein expression in ischemic retina. Studies on mitochondrial DNA (mtDNA) content in ischemic retina showed that there were no statistically significant differences in mtDNA content among control and ischemic groups treated with vehicle or CsA. Therefore, these results provide evidence that the activation of CypD-mediated MPTP opening is associated with the apoptotic pathway and the mitochondrial alteration in RGC death of ischemic retinal injury. On the basis of these observations, our findings suggest that CsA-mediated CypD inhibition may provide a promising therapeutic potential for protecting RGCs against ischemic injury-mediated mitochondrial dysfunction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Caspase 3 / metabolism
  • Cell Survival / drug effects
  • Cyclophilin D
  • Cyclophilins / antagonists & inhibitors*
  • Cyclophilins / metabolism
  • Cyclosporine / pharmacology*
  • Cytoprotection
  • DNA, Mitochondrial / metabolism
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Female
  • High Mobility Group Proteins / metabolism
  • Intraocular Pressure / drug effects
  • Ischemia / enzymology
  • Ischemia / pathology
  • Ischemia / physiopathology
  • Ischemia / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects*
  • Mitochondria / enzymology
  • Mitochondria / pathology
  • Mitochondrial Membrane Transport Proteins / drug effects
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Permeability Transition Pore
  • Neuroprotective Agents / pharmacology*
  • Ocular Hypertension / enzymology
  • Ocular Hypertension / physiopathology
  • Ocular Hypertension / prevention & control
  • Phosphorylation
  • Retinal Diseases / enzymology
  • Retinal Diseases / pathology
  • Retinal Diseases / physiopathology
  • Retinal Diseases / prevention & control*
  • Retinal Ganglion Cells / drug effects*
  • Retinal Ganglion Cells / enzymology
  • Retinal Ganglion Cells / pathology
  • Time Factors
  • bcl-Associated Death Protein / metabolism
  • bcl-X Protein / metabolism

Substances

  • Bad protein, mouse
  • Bcl2l1 protein, mouse
  • Cyclophilin D
  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • High Mobility Group Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Neuroprotective Agents
  • PPIF protein, mouse
  • Tfam protein, mouse
  • bcl-Associated Death Protein
  • bcl-X Protein
  • Cyclosporine
  • Casp3 protein, mouse
  • Caspase 3
  • Cyclophilins