Expression of a truncated form of the endoplasmic reticulum chaperone protein, σ1 receptor, promotes mitochondrial energy depletion and apoptosis

Norifumi Shioda, Kiyoshi Ishikawa, Hideaki Tagashira, Toru Ishizuka, Hiromu Yawo, Kohji Fukunaga

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)

Abstract

The σ1 receptor (σ1R) regulates endoplasmic reticulum (ER)/mitochondrial interorganellar Ca2+ mobilization through the inositol 1,4,5-trisphosphate receptor (IP3R). Here, we observed that expression of a novel splice variant of σ1R, termed short form σ1R (σ1SR), has a detrimental effect on mitochondrial energy production and cell survival. σ1SR mRNA lacks 47 ribonucleotides encoding exon 2, resulting in a frameshift and formation of a truncated receptor. σ1SR localizes primarily in the ER at perinuclear regions and forms a complex with σ1R but not with IP3R in the mitochondrion- associated ER membrane. Overexpression of both σ1R and the truncated isoform promotes mitochondrial elongation with increased ER mitochondrial contact surface. σ1R overexpression increases the efficiency of mitochondrial Ca2+ uptake in response to IP 3R-driven stimuli, whereas σ1SR overexpression reduces it. Most importantly, σ1R promotes ATP production via increased mitochondrial Ca2+ uptake, promoting cell survival in the presence of ER stress. By contrast, σ1SR suppresses ATP production following ER stress, enhancing cell death. Taken together, the newly identified σ1SR isoform interferes with σ1R function relevant to mitochondrial energy production under ER stress conditions, promoting cellular apoptosis.

Original languageEnglish
Pages (from-to)23318-23331
Number of pages14
JournalJournal of Biological Chemistry
Volume287
Issue number28
DOIs
Publication statusPublished - 2012 Jul 6

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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