TY - JOUR
T1 - Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics
AU - Carreras-Sureda, Amado
AU - Jaña, Fabián
AU - Urra, Hery
AU - Durand, Sylvere
AU - Mortenson, David E.
AU - Sagredo, Alfredo
AU - Bustos, Galdo
AU - Hazari, Younis
AU - Ramos-Fernández, Eva
AU - Sassano, Maria L.
AU - Pihán, Philippe
AU - van Vliet, Alexander R.
AU - González-Quiroz, Matías
AU - Torres, Angie K.
AU - Tapia-Rojas, Cheril
AU - Kerkhofs, Martijn
AU - Vicente, Rubén
AU - Kaufman, Randal J.
AU - Inestrosa, Nibaldo C.
AU - Gonzalez-Billault, Christian
AU - Wiseman, R. Luke
AU - Agostinis, Patrizia
AU - Bultynck, Geert
AU - Court, Felipe A.
AU - Kroemer, Guido
AU - Cárdenas, J. César
AU - Hetz, Claudio
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Mitochondria-associated membranes (MAMs) are central microdomains that fine-tune bioenergetics by the local transfer of calcium from the endoplasmic reticulum to the mitochondrial matrix. Here, we report an unexpected function of the endoplasmic reticulum stress transducer IRE1α as a structural determinant of MAMs that controls mitochondrial calcium uptake. IRE1α deficiency resulted in marked alterations in mitochondrial physiology and energy metabolism under resting conditions. IRE1α determined the distribution of inositol-1,4,5-trisphosphate receptors at MAMs by operating as a scaffold. Using mutagenesis analysis, we separated the housekeeping activity of IRE1α at MAMs from its canonical role in the unfolded protein response. These observations were validated in vivo in the liver of IRE1α conditional knockout mice, revealing broad implications for cellular metabolism. Our results support an alternative function of IRE1α in orchestrating the communication between the endoplasmic reticulum and mitochondria to sustain bioenergetics.
AB - Mitochondria-associated membranes (MAMs) are central microdomains that fine-tune bioenergetics by the local transfer of calcium from the endoplasmic reticulum to the mitochondrial matrix. Here, we report an unexpected function of the endoplasmic reticulum stress transducer IRE1α as a structural determinant of MAMs that controls mitochondrial calcium uptake. IRE1α deficiency resulted in marked alterations in mitochondrial physiology and energy metabolism under resting conditions. IRE1α determined the distribution of inositol-1,4,5-trisphosphate receptors at MAMs by operating as a scaffold. Using mutagenesis analysis, we separated the housekeeping activity of IRE1α at MAMs from its canonical role in the unfolded protein response. These observations were validated in vivo in the liver of IRE1α conditional knockout mice, revealing broad implications for cellular metabolism. Our results support an alternative function of IRE1α in orchestrating the communication between the endoplasmic reticulum and mitochondria to sustain bioenergetics.
UR - http://www.scopus.com/inward/record.url?scp=85066097153&partnerID=8YFLogxK
U2 - 10.1038/s41556-019-0329-y
DO - 10.1038/s41556-019-0329-y
M3 - Article
C2 - 31110288
AN - SCOPUS:85066097153
SN - 1465-7392
VL - 21
SP - 755
EP - 767
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 6
ER -