title: Endoplasmic reticulum protein BI-1 regulates Ca²⁺-mediated bioenergetics to promote autophagy.
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.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Renata
authors.initials: R
authors.lastname: Sano
authors.forename: Ying-Chen Claire
authors.initials: YC
authors.lastname: Hou
authors.forename: Michael
authors.initials: M
authors.lastname: Hedvat
authors.forename: Ricardo G
authors.initials: RG
authors.lastname: Correa
authors.forename: Chih-Wen
authors.initials: CW
authors.lastname: Shu
authors.forename: Maryla
authors.initials: M
authors.lastname: Krajewska
authors.forename: Paul W
authors.initials: PW
authors.lastname: Diaz
authors.forename: Craig M
authors.initials: CM
authors.lastname: Tamble
authors.forename: Giovanni
authors.initials: G
authors.lastname: Quarato
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Gottlieb
authors.forename: Masaya
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: David D
authors.initials: DD
authors.lastname: Thomas
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Tait
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Shu-Ichi
authors.initials: S
authors.lastname: Matsuzawa
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004722:Endoribonucleases / Q000378:metabolism; D004734:Energy Metabolism; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010101:Oxygen Consumption; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013290:Streptococcal Infections / Q000276:immunology; D013291:Streptococcus / Q000276:immunology; D013312:Stress, Physiological; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D008565:Membrane Proteins; C484209:TMBIM6 protein, human; C490015:Tmbim6 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium