Abstract
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 Ca2+ reverses the attenuation of thermogenic genes in brown adipocytes with impaired respiratory capacity, while induction of cytosolic Ca2+ is sufficient to attenuate thermogenic gene expression, indicating that cytosolic Ca2+ 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.
Highlights
Brown adipose tissue (BAT) generates heat to combat cold stress[1]
We explored the role of respiratory capacity in thermogenic gene expression by manipulating LRPPRC in an adipose-specific manner and by treating brown adipocytes with an inhibitor of mitochondrial respiration
We provide evidence that this information is transmitted via Ca2+-mediated mitochondrial retrograde signaling, which controls whether brown adipose tissue (BAT) participates in thermogenesis or energy storage
Summary
When activated by cold or β-agonists, BAT oxidizes glucose and lipids (in the form of fatty acids) to fuel uncoupling protein 1 (UCP1)-mediated uncoupled respiration, which drives non-shivering thermogenesis[2]. Due to this unique energy-burning property, BAT has the potential to mitigate obesity[3, 4]. We explored the role of respiratory capacity in thermogenic gene expression by manipulating LRPPRC in an adipose-specific manner and by treating brown adipocytes with an inhibitor of mitochondrial respiration. We provide evidence that this information is transmitted via Ca2+-mediated mitochondrial retrograde signaling, which controls whether BAT participates in thermogenesis or energy storage
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