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Mitochondrial lipoylation integrates age-associated decline in brown fat thermogenesis.
Nature Metabolism ( IF 20.8 ) Pub Date : 2019-09-16 , DOI: 10.1038/s42255-019-0106-z
Kazuki Tajima , Kenji Ikeda , Hsin-Yi Chang , Chih-Hsiang Chang , Takeshi Yoneshiro , Yasuo Oguri , Heejin Jun , Jun Wu , Yasushi Ishihama , Shingo Kajimura

Thermogenesis in brown adipose tissue (BAT) declines with age; however, what regulates this process remains poorly understood. Here, we identify mitochondria lipoylation as a previously unappreciated molecular hallmark of aged BAT in mice. Using mitochondrial proteomics, we show that mitochondrial lipoylation is disproportionally reduced in aged BAT through a post-transcriptional decrease in the iron-sulfur (Fe-S) cluster formation pathway. A defect in the Fe-S cluster formation by the fat-specific deletion of Bola3 significantly reduces mitochondrial lipoylation and fuel oxidation in BAT, leading to glucose intolerance and obesity. In turn, enhanced mitochondrial lipoylation by α-lipoic acid supplementation effectively restores BAT function in old mice, thereby preventing age-associated obesity and glucose intolerance. The effect of α-lipoic acids requires mitochondrial lipoylation via the Bola3 pathway and does not depend on the anti-oxidant activity of α-lipoic acid. These results open up the possibility to alleviate the age-associated decline in energy expenditure by enhancing the mitochondrial lipoylation pathway.

中文翻译:

线粒体脂肪化整合了与年龄相关的棕色脂肪产热下降。

棕色脂肪组织 (BAT) 的生热作用随着年龄的增长而下降;然而,对调节这一过程的因素仍然知之甚少。在这里,我们将线粒体脂肪化确定为小鼠老年 BAT 的一个以前未被重视的分子标志。使用线粒体蛋白质组学,我们表明通过铁硫 (Fe-S) 簇形成途径的转录后减少,老年 BAT 中线粒体脂肪化不成比例地减少。Bola3 脂肪特异性缺失导致的 Fe-S 簇形成缺陷显着降低了 BAT 中的线粒体脂肪化和燃料氧化,导致葡萄糖不耐受和肥胖。反过来,通过补充 α- 硫辛酸增强线粒体脂酰化可有效恢复老年小鼠的 BAT 功能,从而预防与年龄相关的肥胖和葡萄糖耐受不良。α-硫辛酸的作用需要通过 Bola3 途径进行线粒体脂酰化,而不依赖于 α-硫辛酸的抗氧化活性。这些结果开辟了通过增强线粒体脂肪化途径来缓解与年龄相关的能量消耗下降的可能性。
更新日期:2019-09-16
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