Proapoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living synaptic terminals

Elizabeth A. Jonas, John A. Hickman, Mushtaque Chachar, Brian M. Polster, Teresa A. Brandt, Yihru Fannjiang, Iva Ivanovska, Gorka Basañez, Kathleen W. Kinnally, Joshua Zimmerberg, J. Marie Hardwick, Leonard K. Kaczmarek

Research output: Contribution to journalArticlepeer-review

Abstract

Neuronal death is often preceded by functional alterations at nerve terminals. Anti- and proapoptotic BCL-2 family proteins not only regulate the neuronal death pathway but also affect excitability of healthy neurons. We found that exposure of squid stellate ganglia to hypoxia, a death stimulus for neurons, causes a cysteine protease-dependent loss of full-length antiapoptotic BCL-xL, similar to previous findings in mammalian cells. Therefore, to determine the direct effect of the naturally occurring proapoptotic cleavage product of BCL-xL on mitochondria, recombinant N-truncated BCL-xL was applied to mitochondria inside the squid presynaptic terminal and to purified mitochondria isolated from yeast. N-truncated BCL-xL rapidly induced large multi-conductance channels with a maximal conductance significantly larger than those produced by full-length BCL-xL. This activity required the hydrophobic C terminus and the BH3 domain of BCL-xL. Moreover, N-truncated BCL-xL failed to produce any channel activity when applied to plasma membranes, suggesting that a component of the mitochondrial membrane is necessary for its actions. Consistent with this idea, the large channels induced by N-truncated BCL-xL are inhibited by NADH and require the presence of VDAC, a voltage-dependent anion channel present in the outer mitochondrial membrane. These observations suggest that the mitochondrial channels specific to full-length and N-truncated BCL-xL contribute to their opposite effects on synaptic transmission, and are consistent with their opposite effects on the cell death pathway.

Original languageEnglish (US)
Pages (from-to)13590-13595
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number37
DOIs
StatePublished - Sep 14 2004

ASJC Scopus subject areas

  • General

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