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.

			Author Information
			(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
			initiator caspase.

			DOI: 10.1083/jcb.200212059 PMCID: PMC2172754
			PMID: 12668660 [Indexed for MEDLINE]

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