Abstract
The BH3 interacting-domain death agonist (BID) is a pro-apoptotic member of the Bcl-2 protein family. While proteolytic processing of BID links death receptor-induced apoptosis to the mitochondrial apoptosis pathway, we previously showed that full length BID also translocates to mitochondria during Ca2+-induced neuronal cell death. Moreover, mitochondrial carrier homolog 2 (MTCH2) was identified as a mitochondrial protein that interacts with BID during cell death. We started our studies by investigating the effect of Mtch2 silencing in a well-established model of Ca2+-induced mitochondrial permeability transition pore opening in non-neuronal HCT116 cells. We found that silencing of Mtch2 inhibited mitochondrial swelling and the associated decrease in mitochondrial energetics, suggesting a pro-death function for MTCH2 during Ca2+-induced injury. Next, we explored the role of BID and MTCH2 in mediating Ca2+-induced injury in primary cortical neurons triggered by prolonged activation of NMDA glutamate receptors. Analysis of intracellular Ca2+ transients, using time-lapse confocal microscopy, revealed that neurons lacking Bid showed markedly reduced Ca2+ levels during the NMDA excitation period. These Ca2+ transients were further decreased when Mtch2 was also silenced. Collectively, our data suggest that BID and MTCH2 functionally interact to promote Ca2+-induced neuronal injury.
Highlights
The BH3-only protein BH3 interacting-domain death agonist (BID) (BH3-interacting domain death agonist) is a pro-apoptotic member of the Bcl-2 family of proteins
In order to exclude the possibility that apoptosis-induced MOMP contributed to any effects observed, Ca2+-mediated mitochondrial injury was induced in Bax/Bak double-deficient human HCT116 colon cancer cells silenced for Mtch2
We set out to explore the role of BID in neuronal excitotoxicity and how it relates with its interactor mitochondrial carrier homolog 2 (MTCH2), in the setting Ca2+-induced neuronal death
Summary
The BH3-only protein BID (BH3-interacting domain death agonist) is a pro-apoptotic member of the Bcl-2 family of proteins. To tBID, it has been shown that full-length BID is an effective inducer of apoptosis in primary embryonic fibroblasts (Sarig et al, 2003) and translocates to mitochondria in a model of excitotoxic neuronal injury associated with Ca2+ overloading (Ward et al, 2006). This translocation occurred in the absence of cleavage, as detected with a BID-Förster resonance energy transfer (FRET) probe. We investigated the interplay of these two proteins in the settings of Ca2+-induced neuronal injury
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