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.