PubMed Journals: J Cell Biol
Source: PMID: 12668660
⇦ ⇨ J Cell Biol. 2003 Mar 31;160(7):1115-27.
Caspase cleavage product of BAP31 induces
mitochondrial fission through endoplasmic
reticulum calcium signals, enhancing cytochrome
c release to the cytosol.
Breckenridge DG(1), Stojanovic M, Marcellus
RC, Shore GC.
(1) Department of Biochemistry, McGill University,
Montreal, Quebec, Canada H3G 1Y6.
Stimulation of cell surface death receptors
activates caspase-8, which targets a limited
number of substrates including BAP31, an
integral membrane protein of the endoplasmic
reticulum (ER). Recently, we reported that
a caspase-resistant BAP31 mutant inhibited
several features of Fas-induced apoptosis, including
the release of cytochrome c (cyt.c) from
mitochondria (Nguyen, M., D.G. Breckenridge,
A. Ducret, and G.C. Shore. 2000. Mol. Cell.
Biol. 20:6731-6740), implicating ER-mitochondria
crosstalk in this pathway. Here, we report
that the p20 caspase cleavage fragment of
BAP31 can direct pro-apoptotic signals between
the ER and mitochondria. Adenoviral expression
of p20 caused an early release of Ca2+ from
the ER, concomitant uptake of Ca2+ into
mitochondria, and mitochondrial recruitment
of Drp1, a dynamin-related protein that
mediates scission of the outer mitochondrial
membrane, resulting in dramatic fragmentation
and fission of the mitochondrial network.
Inhibition of Drp1 or ER-mitochondrial Ca2+
signaling prevented p20-induced fission
of mitochondria. p20 strongly sensitized
mitochondria to caspase-8-induced cyt.c
release, whereas prolonged expression of
p20 on its own ultimately induced caspase
activation and apoptosis through the mitochondrial
apoptosome stress pathway. Therefore, caspase-8
cleavage of BAP31 at the ER stimulates
Ca2+-dependent mitochondrial fission, enhancing
the release of cyt.c in response to this
DOI: 10.1083/jcb.200212059 PMCID: PMC2172754
PMID: 12668660 [Indexed for MEDLINE]