Role of SERCA1 truncated isoform in the proapoptotic calcium transfer from ER to mitochondria during ER stress

Mol Cell. 2008 Dec 5;32(5):641-51. doi: 10.1016/j.molcel.2008.11.014.


Among the new players at the endoplasmic reticulum (ER)-mitochondria interface regulating interorganelle calcium signaling, those specifically involved during ER stress are not known at present. We report here that the truncated variant of the sarcoendoplasmic reticulum Ca(2+)-ATPase 1 (S1T) amplifies ER stress through the PERK-eIF2alpha-ATF4-CHOP pathway. S1T, which is localized in the ER-mitochondria microdomains, determines ER Ca(2+) depletion due to increased Ca(2+) leak, an increased number of ER-mitochondria contact sites, and inhibition of mitochondria movements. This leads to increased Ca(2+) transfer to mitochondria in both resting and stimulated conditions and activation of the mitochondrial apoptotic pathway. Interestingly, S1T knockdown was shown to prevent ER stress, mitochondrial Ca(2+) overload, and subsequent apoptosis. Thus, by bridging ER stress to apoptosis through increased ER-mitochondria Ca(2+) transfer, S1T acts as an essential determinant of cellular fate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Apoptosis* / drug effects
  • Base Sequence
  • Brefeldin A / pharmacology
  • Calcium / metabolism*
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / enzymology*
  • Endoplasmic Reticulum / pathology*
  • Endoplasmic Reticulum / ultrastructure
  • Enzyme Induction / drug effects
  • Eukaryotic Initiation Factor-2 / metabolism
  • HeLa Cells
  • Homeostasis / drug effects
  • Humans
  • Isoenzymes / metabolism
  • Mitochondria / drug effects
  • Mitochondria / enzymology*
  • Mitochondria / ultrastructure
  • Mitochondrial Membranes / drug effects
  • Mitochondrial Membranes / enzymology
  • Molecular Sequence Data
  • Mutation / genetics*
  • Response Elements / genetics
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / biosynthesis
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*
  • eIF-2 Kinase / metabolism


  • Eukaryotic Initiation Factor-2
  • Isoenzymes
  • Activating Transcription Factor 4
  • Brefeldin A
  • PERK kinase
  • eIF-2 Kinase
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • ATP2A1 protein, human
  • Calcium