Mitochondrial retrograde signaling connects respiratory capacity to thermogenic gene expression.

Mitochondrial respiration plays a crucial role in determining the metabolic state of brown adipose tissue (BAT), due to its direct roles in thermogenesis, as well as through additional mechanisms. Here, we show that respiration-dependent retrograde signaling from mitochondria to nucleus contributes to genetic and metabolic reprogramming of BAT. In mouse BAT, ablation of LRPPRC (LRP130), a potent regulator of mitochondrial transcription and respiratory capacity, triggers down-regulation of thermogenic genes, promoting a storage phenotype in BAT. This retrograde regulation functions by inhibiting the recruitment of PPARγ to the regulatory elements of thermogenic genes. Reducing cytosolic Ca reverses the attenuation of thermogenic genes in brown adipocytes with impaired respiratory capacity, while induction of cytosolic Ca is sufficient to attenuate thermogenic gene expression, indicating that cytosolic Ca mediates mitochondria-nucleus crosstalk. Our findings suggest respiratory capacity governs thermogenic gene expression and BAT function via mitochondria-nucleus communication, which in turn leads to either a thermogenic or storage mode.