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Exp Neurol. 2009 Aug;218(2):221-7. doi: 10.1016/j.expneurol.2009.04.013. Epub 2009 Apr 23.

Mitochondrial micro-calpain is not involved in the processing of apoptosis-inducing factor.

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1
Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, USA.

Abstract

Caspase-independent cell death, an important death pathway in many cells including neurons, is executed via apoptosis-inducing factor (AIF), an oxidoreductase, localized to the mitochondrial intermembrane space. AIF is processed and released from mitochondria following mitochondrial permeability transition pore (mPTP) formation, and translocates to the nucleus to induce DNA fragmentation and cell death. The release of AIF requires cleavage of its N-terminus anchored in the inner mitochondrial membrane. The protease responsible for this AIF truncation has not been established, although there is considerable evidence suggesting a role for micro-calpain. We previously found that a pool of micro-calpain is localized to the mitochondrial intermembrane space, the submitochondrial compartment in which AIF truncation occurs. The close submitochondrial proximity of mitochondrial micro-calpain and AIF gives support to the hypothesis that mitochondrial micro-calpain may be the protease responsible for processing AIF prior to its release. In the present study, AIF was released from rat liver mitochondria following mPTP induction by atractyloside. This release was inhibited by the cysteine protease inhibitor MDL28170, but not by more specific calpain inhibitors PD150606 and calpastatin. Atractyloside caused swelling in rat brain mitochondria, but did not induce AIF release. In a mitochondrial fraction from SH-SY5Y neuroblastoma cells, incubation with 5 mM Ca(2+) resulted in the activation of micro-calpain but not in AIF truncation. In summary, the localization of micro-calpain to the mitochondrial intermembrane space is suggestive of its possible involvement in AIF processing, but direct experimental evidence supporting such a role has been elusive.

PMID:
19393648
PMCID:
PMC2756010
DOI:
10.1016/j.expneurol.2009.04.013
[Indexed for MEDLINE]
Free PMC Article

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