Mitochondrial retrograde signaling connects respiratory capacity to thermogenic gene expression.
Mitochondrial retrograde signaling connects respiratory capacity to thermogenic gene expression.
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DOI：
10.1038/s41598-017-01879-x
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发表时间：
2017-05-17
影响因子：
4.6
通讯作者：
Cooper MP
中科院分区：
文献类型：
--
作者：
Nam M;Akie TE;Sanosaka M;Craige SM;Kant S;Keaney JF Jr;Cooper MP
线粒体呼吸在确定棕色脂肪组织（BAT）的代谢状态中起着至关重要的作用，这是由于它在产热中的直接作用，以及通过其他机制。在这里，我们发现从线粒体到细胞核的呼吸依赖逆行信号有助于BAT的遗传和代谢重编程。在小鼠BAT中，LRPPRC (LRP130)（线粒体转录和呼吸能力的有效调节因子）的消融触发了产热基因的下调，促进了BAT的储存表型。这种逆行调节通过抑制PPARγ对产热基因调控元件的募集而起作用。在呼吸能力受损的棕色脂肪细胞中，胞质Ca2+的减少逆转了产热基因的衰减，而胞质Ca2+的诱导足以减弱产热基因的表达，这表明胞质Ca2+介导了线粒体-核串扰。我们的研究结果表明，呼吸能力通过线粒体-核通信控制产热基因表达和BAT功能，这反过来又导致产热或储存模式。
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.