Mitochondrial lipoylation integrates age-associated decline in brown fat thermogenesis

K Tajima, K Ikeda, HY Chang, CH Chang… - Nature …, 2019 - nature.com
K Tajima, K Ikeda, HY Chang, CH Chang, T Yoneshiro, Y Oguri, H Jun, J Wu, Y Ishihama
Nature metabolism, 2019nature.com
Thermogenesis in brown adipose tissue (BAT) declines with age; however, what regulates
this process is poorly understood. Here, we identify mitochondrial 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 Fe–
S cluster formation by the fat-specific deletion of Bola3 significantly reduces mitochondrial …
Abstract
Thermogenesis in brown adipose tissue (BAT) declines with age; however, what regulates this process is poorly understood. Here, we identify mitochondrial 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 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 antioxidant activity of α-lipoic acid. These results open up the possibility of alleviating age-associated decline in energy expenditure by enhancing the mitochondrial lipoylation pathway.
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