Exploring the In Vivo Role of the Mitochondrial Calcium Uniporter in Brown Fat Bioenergetics

Cell Rep. 2019 Apr 30;27(5):1364-1375.e5. doi: 10.1016/j.celrep.2019.04.013.


The mitochondrial calcium uniporter has been proposed to coordinate the organelle's energetics with calcium signaling. Uniporter current has previously been reported to be extremely high in brown adipose tissue (BAT), yet it remains unknown how the uniporter contributes to BAT physiology. Here, we report the generation and characterization of a mouse model lacking Mcu, the pore forming subunit of the uniporter, specifically in BAT (BAT-Mcu-KO). BAT-Mcu-KO mice lack uniporter-based calcium uptake in BAT mitochondria but exhibit unaffected cold tolerance, diet-induced obesity, and transcriptional response to cold in BAT. Unexpectedly, we found in wild-type animals that cold powerfully activates the ATF4-dependent integrated stress response (ISR) in BAT and upregulates circulating FGF21 and GDF15, raising the hypothesis that the ISR partly underlies the pleiotropic effects of BAT on systemic metabolism. Our study demonstrates that the uniporter is largely dispensable for BAT thermogenesis and demonstrates activation of the ISR in BAT in response to cold.

Keywords: ATF4; FGF21; GDF15; MCU; brown fat; calcium; integrated stress response; mitochondria; thermogenesis; uniporter.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Adipose Tissue, Brown / metabolism*
  • Animals
  • Calcium / metabolism
  • Calcium Channels / genetics*
  • Cell Line
  • Cold-Shock Response*
  • Diet, High-Fat / adverse effects
  • Energy Metabolism
  • Female
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism
  • Growth Differentiation Factor 15 / genetics
  • Growth Differentiation Factor 15 / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics*
  • Obesity / etiology
  • Obesity / genetics
  • Thermogenesis*


  • Atf4 protein, mouse
  • Calcium Channels
  • Gdf15 protein, mouse
  • Growth Differentiation Factor 15
  • Mcu protein, mouse
  • Mitochondrial Proteins
  • fibroblast growth factor 21
  • Activating Transcription Factor 4
  • Fibroblast Growth Factors
  • Calcium