Postnatal brain development and neural cell differentiation modulate mitochondrial Bax and BH3 peptide-induced cytochrome c release.
Bax mediates cytochrome c release and apoptosis during neurodevelopment. Brain mitochondria that were isolated from 8-day, 17-day, and adult rats displayed decreasing levels of mitochondrial Bax. The amount of cytochrome c released from brain mitochondria by a peptide containing the BH3 cell death domain decreased with increasing age. However, approximately 60% of cytochrome c in adult brain mitochondria could be released by the BH3 peptide in the presence of exogenous human recombinant Bax. Mitochondrial Bax was downregulated in PC12S neural cells differentiated with nerve growth factor, and mitochondria isolated from these cells demonstrated decreased sensitivity to BH3-peptide-induced cytochrome c release. These results demonstrate that immature brain mitochondria and mitochondria from undifferentiated neural cells are particularly sensitive to cytochrome c release mediated by endogenous Bax and a BH3 death domain peptide. Postnatal developmental changes in mitochondrial Bax levels may contribute to the increased susceptibility of neurons to pathological apoptosis in immature animals.
Polster
B M
BM
Department of Anesthesiology, University of Maryland School of Medicine, Baltimore 21201, USA.
Robertson
C L
CL
Bucci
C J
CJ
Suzuki
M
M
Fiskum
G
G
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015151:Immunoblotting; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D051028:bcl-2-Associated X Protein
C474007:Bax protein (53-86); C494828:Bax protein, rat; D010446:Peptide Fragments; D010455:Peptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c