Postnatal developmental regulation of Bcl-2 family proteins in brain mitochondria.

Although it has been long recognized that the relative balance of pro- and antiapoptotic Bcl-2 proteins is critical in determining the susceptibility to apoptotic death, only a few studies have examined the level of these proteins specifically at mitochondria during postnatal brain development. In this study, we examined the age-dependent regulation of Bcl-2 family proteins using rat brain mitochondria isolated at various postnatal ages and from the adult. The results indicate that a general down-regulation of most of the proapoptotic Bcl-2 proteins present in mitochondria occurs during postnatal brain development. The multidomain proapoptotic Bax, Bak, and Bok are all expressed at high levels in mitochondria early postnatally but decline in the adult. Multiple BH3-only proteins, including direct activators (Bid, Bim, and Puma) and the derepressor BH3-only protein Bad, are also present in immature brain mitochondria and are down-regulated in the adult brain. Antiapoptotic Bcl-2 family members are differentially regulated, with a shift from high Bcl-2 expression in immature mitochondria to predominant Bcl-x(L) expression in the adult. These results support the concept that developmental differences in upstream regulators of the mitochondrial apoptotic pathway are responsible for the increased susceptibility of cells in the immature brain to apoptosis following injury.