Mitochondrial lipoylation integrates age- associated decline in brown fat thermogenesis

Kazuki Tajima1,2,3, Kenji Ikeda1,2,3,7, Hsin-Yi Chang4,8, Chih-Hsiang Chang4, Takeshi Yoneshiro1,2,3, Yasuo Oguri1,2,3, Heejin Jun5, Jun Wu5,6, Yasushi Ishihama4 and Shingo Kajimura 1,2,3
Nat Metab.
Publication Date: 
Mon, 2019-09-16
1University of California, San Francisco Diabetes Center, San Francisco, CA, USA. 2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA, USA. 3Department of Cell and Tissue Biology, University of California, San Francisco, CA, USA. 4Department of Molecular and Cellular Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan. 5Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA. 6Department of Molecular & Integrative Physiology, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA. 7Present address: Department of Molecular Endocrionology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan. 8Present address: Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan
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.