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

  1. John C. Reed1,8
  1. 1Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA;
  2. 2BioScience Center, San Diego State University, San Diego, California 92182, USA;
  3. 3Department of Pediatrics, School of Medicine,
  4. 4Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, California, 92093 USA;
  5. 5Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA;
  6. 6Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 92105, USA;
  7. 7Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298, USA

    Abstract

    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.

    Keywords

    Footnotes

    • Received November 28, 2011.
    • Accepted March 29, 2012.
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