Endoplasmic reticulum protein BI-1 regulates Ca2+-mediated bioenergetics to promote autophagy

Renata Sano, Ying Chen Claire Hou, Michael Hedvat, Ricardo G. Correa, Chih Wen Shu, Maryla Krajewska, Paul W. Diaz, Craig M. Tamble, Giovanni Quarato, Roberta A. Gottlieb, Masaya Yamaguchi, Victor Nizet, Russell Dahl, David D. Thomas, Stephen W. Tait, Douglas R. Green, Paul B. Fisher, Shu Ichi Matsuzawa, John C. Reed

Research output: Contribution to journalArticlepeer-review

80 Scopus citations


Autophagy is a lysosomal degradation pathway that converts macromolecules into substrates for energy production during nutrient-scarce conditions such as those encountered in tumor microenvironments. Constitutive mitochondrial uptake of endoplasmic reticulum (ER) Ca2+ mediated by inositol triphosphate receptors (IP3Rs) maintains cellular bioenergetics, thus suppressing autophagy. We show that the ER membrane protein Bax inhibitor-1 (BI-1) promotes autophagy in an IP3R-dependent manner. By reducing steady-state levels of ER Ca2+ via IP3Rs, BI-1 influences mitochondrial bioenergetics, reducing oxygen consumption, impacting cellular ATP levels, and stimulating autophagy. Furthermore, BI-1-deficient mice show reduced basal autophagy, and experimentally reducing BI-1 expression impairs tumor xenograft growth in vivo. BI-1's ability to promote autophagy could be dissociated from its known function as a modulator of IRE1 signaling in the context of ER stress. The results reveal BI-1 as a novel autophagy regulator that bridges Ca2+ signaling between ER and mitochondria, reducing cellular oxygen consumption and contributing to cellular resilience in the face of metabolic stress.

Original languageEnglish (US)
Pages (from-to)1041-1054
Number of pages14
JournalGenes and Development
Issue number10
StatePublished - May 15 2012


  • Autophagy
  • BI-1
  • Bioenergetics
  • Ca
  • ER stress


Dive into the research topics of 'Endoplasmic reticulum protein BI-1 regulates Ca2+-mediated bioenergetics to promote autophagy'. Together they form a unique fingerprint.

Cite this