Abstract
Mitochondrial cytochrome c release and inositol (1,4,5) trisphosphate receptor (InsP(3)R)-mediated calcium release from the endoplasmic reticulum mediate apoptosis in response to specific stimuli. Here we show that cytochrome c binds to the InsP(3)R during apoptosis. Addition of 1 nM cytochrome c blocks calcium-dependent inhibition of InsP(3)R function. Early in apoptosis, cytochrome c translocates to the endoplasmic reticulum where it selectively binds InsP(3)R, resulting in sustained, oscillatory cytosolic calcium increases. These calcium events are linked to the coordinate release of cytochrome c from all mitochondria. Our findings identify a feed-forward mechanism whereby early cytochrome c release increases InsP(3)R function, resulting in augmented cytochrome c release that amplifies the apoptotic signal.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology*
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Binding Sites / drug effects
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Binding Sites / physiology
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Biological Clocks / drug effects
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Biological Clocks / physiology
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Calcium / metabolism*
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Calcium Channels / metabolism*
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Calcium Signaling / drug effects
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Calcium Signaling / physiology*
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Cytochromes c / metabolism*
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Cytochromes c / pharmacology
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Cytosol / drug effects
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Cytosol / metabolism
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / metabolism
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Feedback, Physiological / drug effects
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Feedback, Physiological / physiology
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HeLa Cells
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Humans
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Inositol 1,4,5-Trisphosphate Receptors
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Mitochondria / drug effects
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Mitochondria / metabolism
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Rats
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology
Substances
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Calcium Channels
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ITPR1 protein, human
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Inositol 1,4,5-Trisphosphate Receptors
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Receptors, Cytoplasmic and Nuclear
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Cytochromes c
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Calcium