Abstract
Controversy surrounds proper classification of neurodegeneration occurring acutely following neonatal hypoxia-ischemia (HI). By ultrastructural classification, in the first 24 h after neonatal hypoxia-ischemia in the 7-day-old (p7) rat, the majority of striatal cells die having both apoptotic and necrotic features. There is formation of a functional apoptosome, and activation of caspases-9 and -3 occurring simultaneously with loss of structurally intact mitochondria to 34.7±25% and loss of mitochondrial cytochrome c oxidase activity to 34.7±12.7% of control levels by 3 h after hypoxia-ischemia. There is also loss of the mitochondrial motor protein, kinesin. This combination of activation of apoptosis pathways simultaneous with significant mitochondrial dysfunction may cause incomplete packaging of nuclear and cytoplasmic contents and a hybrid of necrotic and apoptotic features. Evidence for an intermediate biochemistry of cell death including expression of the 17 kDa isoform of caspase-3 in dying neurons lacking a classic apoptotic morphology and degradation of the neuronal cytoskeletal protein spectrin by caspase-3 and calcium-activated calpains yielding 120 kDa and 145/150 kDa fragments, respectively, is also found. In summary, neonatal hypoxia-ischemia triggers apoptotic cascades, and simultaneously causes mitochondrial structural and functional failure. The presence of a "continuum" phenotype of cell death that varies on a cell-by-cell basis suggests that the phenotype of cell death is dependent on the energy available to drive the apoptotic pathways to completion.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 822-833 |
| Number of pages | 12 |
| Journal | Neuroscience |
| Volume | 149 |
| Issue number | 4 |
| DOIs | |
| State | Published - Nov 23 2007 |
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Keywords
- continuum cell death
- mitochondria
- neonatal brain injury
- neurodegeneration
- ultrastructure
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
Failure to complete apoptosis following neonatal hypoxia-ischemia manifests as "continuum" phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain. / Northington, Frances; Zelaya, M. E.; O'Riordan, D. P.; Blomgren, K.; Flock, D. L.; Hagberg, H.; Ferriero, D. M.; Martin, Lee J.
In: Neuroscience, Vol. 149, No. 4, 23.11.2007, p. 822-833.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Failure to complete apoptosis following neonatal hypoxia-ischemia manifests as "continuum" phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain
AU - Northington, Frances
AU - Zelaya, M. E.
AU - O'Riordan, D. P.
AU - Blomgren, K.
AU - Flock, D. L.
AU - Hagberg, H.
AU - Ferriero, D. M.
AU - Martin, Lee J
PY - 2007/11/23
Y1 - 2007/11/23
N2 - Controversy surrounds proper classification of neurodegeneration occurring acutely following neonatal hypoxia-ischemia (HI). By ultrastructural classification, in the first 24 h after neonatal hypoxia-ischemia in the 7-day-old (p7) rat, the majority of striatal cells die having both apoptotic and necrotic features. There is formation of a functional apoptosome, and activation of caspases-9 and -3 occurring simultaneously with loss of structurally intact mitochondria to 34.7±25% and loss of mitochondrial cytochrome c oxidase activity to 34.7±12.7% of control levels by 3 h after hypoxia-ischemia. There is also loss of the mitochondrial motor protein, kinesin. This combination of activation of apoptosis pathways simultaneous with significant mitochondrial dysfunction may cause incomplete packaging of nuclear and cytoplasmic contents and a hybrid of necrotic and apoptotic features. Evidence for an intermediate biochemistry of cell death including expression of the 17 kDa isoform of caspase-3 in dying neurons lacking a classic apoptotic morphology and degradation of the neuronal cytoskeletal protein spectrin by caspase-3 and calcium-activated calpains yielding 120 kDa and 145/150 kDa fragments, respectively, is also found. In summary, neonatal hypoxia-ischemia triggers apoptotic cascades, and simultaneously causes mitochondrial structural and functional failure. The presence of a "continuum" phenotype of cell death that varies on a cell-by-cell basis suggests that the phenotype of cell death is dependent on the energy available to drive the apoptotic pathways to completion.
AB - Controversy surrounds proper classification of neurodegeneration occurring acutely following neonatal hypoxia-ischemia (HI). By ultrastructural classification, in the first 24 h after neonatal hypoxia-ischemia in the 7-day-old (p7) rat, the majority of striatal cells die having both apoptotic and necrotic features. There is formation of a functional apoptosome, and activation of caspases-9 and -3 occurring simultaneously with loss of structurally intact mitochondria to 34.7±25% and loss of mitochondrial cytochrome c oxidase activity to 34.7±12.7% of control levels by 3 h after hypoxia-ischemia. There is also loss of the mitochondrial motor protein, kinesin. This combination of activation of apoptosis pathways simultaneous with significant mitochondrial dysfunction may cause incomplete packaging of nuclear and cytoplasmic contents and a hybrid of necrotic and apoptotic features. Evidence for an intermediate biochemistry of cell death including expression of the 17 kDa isoform of caspase-3 in dying neurons lacking a classic apoptotic morphology and degradation of the neuronal cytoskeletal protein spectrin by caspase-3 and calcium-activated calpains yielding 120 kDa and 145/150 kDa fragments, respectively, is also found. In summary, neonatal hypoxia-ischemia triggers apoptotic cascades, and simultaneously causes mitochondrial structural and functional failure. The presence of a "continuum" phenotype of cell death that varies on a cell-by-cell basis suggests that the phenotype of cell death is dependent on the energy available to drive the apoptotic pathways to completion.
KW - continuum cell death
KW - mitochondria
KW - neonatal brain injury
KW - neurodegeneration
KW - ultrastructure
UR - http://www.scopus.com/inward/record.url?scp=36248945038&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=36248945038&partnerID=8YFLogxK
U2 - 10.1016/j.neuroscience.2007.06.060
DO - 10.1016/j.neuroscience.2007.06.060
M3 - Article
C2 - 17961929
AN - SCOPUS:36248945038
VL - 149
SP - 822
EP - 833
JO - Neuroscience
JF - Neuroscience
SN - 0306-4522
IS - 4
ER -