Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU.
Cytosolic Ca2+ signals, generated through the coordinated translocation of Ca2+ across the plasma membrane (PM) and endoplasmic reticulum (ER) membrane, mediate diverse cellular responses. Mitochondrial Ca2+ is important for mitochondrial function, and when cytosolic Ca2+ concentration becomes too high, mitochondria function as cellular Ca2+ sinks. By measuring mitochondrial Ca2+ currents, we found that mitochondrial Ca2+ uptake was reduced in chicken DT40 B lymphocytes lacking either the ER-localized inositol trisphosphate receptor (IP3R), which releases Ca2+ from the ER, or Orai1 or STIM1, components of the PM-localized Ca2+ -permeable channel complex that mediates store-operated calcium entry (SOCE) in response to depletion of ER Ca2+ stores. The abundance of MCU, the pore-forming subunit of the mitochondrial Ca2+ uniporter, was reduced in cells deficient in IP3R, STIM1, or Orai1. Chromatin immunoprecipitation and promoter reporter analyses revealed that the Ca2+ -regulated transcription factor CREB (cyclic adenosine monophosphate response element-binding protein) directly bound the MCU promoter and stimulated expression. Lymphocytes deficient in IP3R, STIM1, or Orai1 exhibited altered mitochondrial metabolism, indicating that Ca2+ released from the ER and SOCE-mediated signals modulates mitochondrial function. Thus, our results showed that a transcriptional regulatory circuit involving Ca2+ -dependent activation of CREB controls the Ca2+ uptake capability of mitochondria and hence regulates mitochondrial metabolism.
Department of Biochemistry, Temple University, Philadelphia, PA 19140, USA. Center for Translational Medicine, Temple University, Philadelphia, PA 19140, USA.
Santhanam
S
Shanmughapriya
Department of Biochemistry, Temple University, Philadelphia, PA 19140, USA. Center for Translational Medicine, Temple University, Philadelphia, PA 19140, USA.
Sudarsan
S
Rajan
Department of Biochemistry, Temple University, Philadelphia, PA 19140, USA. Center for Translational Medicine, Temple University, Philadelphia, PA 19140, USA.
Nicholas E
NE
Hoffman
Center for Translational Medicine, Temple University, Philadelphia, PA 19140, USA.
Xueqian
X
Zhang
Department of Biochemistry, Temple University, Philadelphia, PA 19140, USA. Center for Translational Medicine, Temple University, Philadelphia, PA 19140, USA.
Shuchi
S
Guo
Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
Jill E
JE
Kolesar
Department of Biochemistry, Temple University, Philadelphia, PA 19140, USA. Center for Translational Medicine, Temple University, Philadelphia, PA 19140, USA.
Kevin J
KJ
Hines
Department of Biochemistry, Temple University, Philadelphia, PA 19140, USA. Center for Translational Medicine, Temple University, Philadelphia, PA 19140, USA.
Jonathan
J
Ragheb
Department of Medicine, Temple University, Philadelphia, PA 19140, USA.
Neelakshi R
NR
Jog
Department of Medicine, Temple University, Philadelphia, PA 19140, USA.
Roberto
R
Caricchio
Laboratory of Lymphocyte Differentiation, World Premiere International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Yoshihiro
Y
Baba
Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA 17033, USA.
Yandong
Y
Zhou
Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
Brett A
BA
Kaufman
Center for Translational Medicine, Temple University, Philadelphia, PA 19140, USA.
Joseph Y
JY
Cheung
Laboratory of Lymphocyte Differentiation, World Premiere International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Tomohiro
T
Kurosaki
Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA 17033, USA. madeshm@temple.edu dongill@psu.edu.
Donald L
DL
Gill
Department of Biochemistry, Temple University, Philadelphia, PA 19140, USA. Center for Translational Medicine, Temple University, Philadelphia, PA 19140, USA. madeshm@temple.edu dongill@psu.edu.
Muniswamy
M
Madesh
D000818:Animals; D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D002645:Chickens; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D000071740:ORAI1 Protein; D000071737:Stromal Interaction Molecule 1
D030161:Avian Proteins; D015220:Calcium Channels; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D024101:Mitochondrial Proteins; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; C034703:mitochondrial calcium uniporter