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Outer mitochondrial membrane localization of apoptosis-inducing factor: mechanistic implications for release
- Source :
- ASN NEURO, ASN Neuro, Vol 1 (2009)
- Publication Year :
- 2009
- Publisher :
- American Society for Neurochemistry, 2009.
-
Abstract
- Poly(ADP-ribose) polymerase-1-dependent cell death (known as parthanatos) plays a pivotal role in many clinically important events including ischaemia/reperfusion injury and glutamate excitotoxicity. A recent study by us has shown that uncleaved AIF (apoptosis-inducing factor), but not calpain-hydrolysed truncated-AIF, was rapidly released from the mitochondria during parthanatos, implicating a second pool of AIF that might be present in brain mitochondria contributing to the rapid release. In the present study, a novel AIF pool is revealed in brain mitochondria by multiple biochemical analyses. Approx. 30% of AIF loosely associates with the outer mitochondrial membrane on the cytosolic side, in addition to its main localization in the mitochondrial intermembrane space attached to the inner membrane. Immunogold electron microscopic analysis of mouse brain further supports AIF association with the outer, as well as the inner, mitochondrial membrane in vivo. In line with these observations, approx. 20% of uncleaved AIF rapidly translocates to the nucleus and functionally causes neuronal death upon NMDA ( N-methyl-d-aspartate) treatment. In the present study we show for the first time a second pool of AIF in brain mitochondria and demonstrate that this pool does not require cleavage and that it contributes to the rapid release of AIF. Moreover, these results suggest that this outer mitochondrial pool of AIF is sufficient to cause cell death during parthanatos. Interfering with the release of this outer mitochondrial pool of AIF during cell injury paradigms that use parthanatos hold particular promise for novel therapies to treat neurological disorders.
- Subjects :
- Programmed cell death
S1
cyt c, cytochrome c
Mitochondrial intermembrane space
ROI, region of interest
Excitotoxicity
ANT, adenine nucleotide translocator
Mitochondrion
Biology
poly(ADP-ribose) polymerase-1
medicine.disease_cause
S3
lcsh:RC321-571
Smac, second mitochondrial-derived activator of caspase
PARP-1, poly(ADP-ribose) polymerase-1
03 medical and health sciences
0302 clinical medicine
parthanatos
medicine
Inner membrane
mitochondrion
cardiovascular diseases
MnSOD, manganese superoxide dismutase
Inner mitochondrial membrane
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
030304 developmental biology
0303 health sciences
immunogold electron microscopy
General Neuroscience
NMDA, N-methyl-d-aspartate
Tim23, translocase of inner membrane 23
Tom20, translocase of outer membrane 20
WT, wild-type
S11
Cell biology
AIF, apoptosis-inducing factor
Cytosol
Hq, Harlequin
VDAC, voltage-dependent anion channel
Apoptosis-inducing factor
Neurology (clinical)
biological phenomena, cell phenomena, and immunity
030217 neurology & neurosurgery
apoptosis-inducing factor (AIF)
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 17590914
- Volume :
- 1
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- ASN NEURO
- Accession number :
- edsair.doi.dedup.....65c3195c600b2d19ca1691a1d69d9c84