Mitochondrial lipoylation integrates age-associated decline in brown fat thermogenesis

Kazuki Tajima, Kenji Ikeda, Hsin Yi Chang, Chih Hsiang Chang, Takeshi Yoneshiro, Yasuo Oguri, Heejin Jun, Jun Wu, Yasushi Ishihama, Shingo Kajimura

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)886-898
Number of pages13
JournalNature Metabolism
Volume1
Issue number9
DOIs
Publication statusPublished - Sep 1 2019

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Internal Medicine
  • Cell Biology

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    Tajima, K., Ikeda, K., Chang, H. Y., Chang, C. H., Yoneshiro, T., Oguri, Y., Jun, H., Wu, J., Ishihama, Y., & Kajimura, S. (2019). Mitochondrial lipoylation integrates age-associated decline in brown fat thermogenesis. Nature Metabolism, 1(9), 886-898. https://doi.org/10.1038/s42255-019-0106-z