Developmental shift of cyclophilin D contribution to hypoxic-ischemic brain injury.
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.
Wang
Xiaoyang
X
Perinatal Center, University of Gothenburg, SE-405 30 Gothenburg, Sweden. xiaoyang.wang@fysiologi.gu.se
Carlsson
Ylva
Y
Basso
Emy
E
Zhu
Changlian
C
Rousset
Catherine I
CI
Rasola
Andrea
A
Johansson
Bengt R
BR
Blomgren
Klas
K
Mallard
Carina
C
Bernardi
Paolo
P
Forte
Michael A
MA
Hagberg
Henrik
H
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D001930:Brain Injuries / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency / Q000502:physiology*; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D020925:Hypoxia-Ischemia, Brain / Q000150:complications*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D010446:Peptide Fragments / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D051033:Apoptosis Inducing Factor; C474007:Bax protein (53-86); C494827:Bax protein, mouse; D000081406:Peptidyl-Prolyl Isomerase F; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; C000631446:PPIF protein, mouse; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020169:Caspases; D021983:Cyclophilins