Expression of a Truncated Form of the Endoplasmic Reticulum Chaperone Protein, σ1 Receptor, Promotes Mitochondrial Energy Depletion and Apoptosis

The sigma 1 receptor (sigma R-1) 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 sigma R-1, termed short form sigma R-1 (sigma 1SR), has a detrimental effect on mitochondrial energy production and cell survival. sigma 1SR mRNA lacks 47 ribo-nucleotides encoding exon 2, resulting in a frameshift and formation of a truncated receptor. sigma 1SR localizes primarily in the ER at perinuclear regions and forms a complex with sigma R-1 but not with IP3R in the mitochondrion-associated ER membrane. Overexpression of both sigma R-1 and the truncated isoform promotes mitochondrial elongation with increased ER mitochondrial contact surface. sigma R-1 overexpression increases the efficiency of mitochondrial Ca2+ uptake in response to IP3R-driven stimuli, whereas sigma 1SR overexpression reduces it. Most importantly, sigma R-1 promotes ATP production via increased mitochondrial Ca2+ uptake, promoting cell survival in the presence of ER stress. By contrast, sigma 1SR suppresses ATP production following ER stress, enhancing cell death. Taken together, the newly identified sigma 1SR isoform interferes with sigma R-1 function relevant to mitochondrial energy production under ER stress conditions, promoting cellular apoptosis.