The mitochondrial calcium uniporter engages UCP1 to form a thermoporter that promotes thermogenesis.

Abstract

Uncoupling protein 1 (UCP1)-mediated adaptive thermogenesis protects mammals against hypothermia and metabolic dysregulation. Whether and how mitochondrial calcium regulates this process remains unclear. Here, we show that mitochondrial calcium uniporter (MCU) recruits UCP1 through essential MCU regulator (EMRE) to form an MCU-EMRE-UCP1 complex upon adrenergic stimulation. This complex formation increases mitochondrial calcium uptake to accelerate the tricarboxylic acid cycle and supply more protons that promote uncoupled respiration, functioning as a thermogenic uniporter. Mitochondrial calcium uptake 1 (MICU1) negatively regulates thermogenesis probably through inhibiting thermogenic uniporter formation. Accordingly, the deletion of Mcu or Emre in brown adipocytes markedly impairs thermogenesis and exacerbates obesity and metabolic dysfunction. Remarkably, the enhanced assembly of the thermogenic uniporter via Micu1 knockout or expressing linked EMRE-UCP1 results in opposite phenotypes. Thus, we have uncovered a "thermoporter" that provides a driving force for the UCP1 operation in thermogenesis, which could be leveraged to combat obesity and associated metabolic disorders.