Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU

Cytosolic Ca 2+ signals, generated through the coordinated translocation of Ca 2+ across the plasma membrane (PM) and endoplasmic reticulum (ER) membrane, mediate diverse cellular responses. Mitochondrial Ca 2+ is important for mitochondrial function, and when cytosolic Ca 2+ concentration becomes too high, mitochondria function as cellular Ca 2+ sinks. By measuring mitochondrial Ca 2+ currents, we found that mitochondrial Ca 2+ uptake was reduced in chicken DT40 B lymphocytes lacking either the ER-localized inositol trisphosphate receptor (IP 3 R), which releases Ca 2+ from the ER, or Orai1 or STIM1, components of the PM-localized Ca 2+ -permeable channel complex that mediates store-operated calcium entry (SOCE) in response to depletion of ER Ca 2+ stores. The abundance of MCU, the pore-forming subunit of the mitochondrial Ca 2+ uniporter, was reduced in cells deficient in IP 3 R, STIM1, or Orai1. Chromatin immunoprecipitation and promoter reporter analyses revealed that the Ca 2+ -regulated transcription factor CREB (cyclic adenosine monophosphate response element–binding protein) directly bound the MCU promoter and stimulated expression. Lymphocytes deficient in IP 3 R, STIM1, or Orai1 exhibited altered mitochondrial metabolism, indicating that Ca 2+ released from the ER and SOCE-mediated signals modulates mitochondrial function. Thus, our results showed that a transcriptional regulatory circuit involving Ca 2+ -dependent activation of CREB controls the Ca 2+ uptake capability of mitochondria and hence regulates mitochondrial metabolism.