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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Data availability
The proteomics data used in this study have been deposited with the ProteomeXchange Consortium under accession nos. PXD013410 (Age-associated mouse brown adipose tissue mitochondrial proteome), PXD014143 (Bola3 KO mouse brown adipose tissue mitochondrial proteome) and PXD014080 (Lipoylated proteins complex in mouse brown adipose tissue). The RNA-Seq data have been deposited with ArrayExpress under accession no. E-MTAB-7445 (RNA-Seq of age-associated transcriptome changes in brown adipose tissue). The data supporting the findings of this study are available from the corresponding author upon request.
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Acknowledgements
We are grateful to T. Huynh and Y. Seo at the UCSF Imaging Center for their support in the [18F]-FDG PET–CT imaging, C. Paillart for his support in the Comprehensive Lab Animal Monitoring System study, Z. Brown for his editorial help and R. Panda and S. Giacometti for their support in the analysis for RNA-Seq. We also thank T. Hagen at the Linus Pauling Institute for his suggestions. This work was supported by National Institutes of Health (NIH) grants (nos. DK97441 and DK108822), the NIH Office of Dietary Supplements and the Edward Mallinckrodt, Jr. Foundation to S.K., NIH grant no. DK107583 to J.W. and a JSPS grants-in-aid for scientific research grant (no. 17H03605) to H-Y.C and Y.I. K.T., K.I. and Y.O. are supported by the Manpei Suzuki Diabetes Foundation. T.Y. is supported by the JSPS Overseas Research Fellowship.
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K.T. and S.K. conceived the study and designed the experiments. K.T., K.I., T.Y. and Y.O. performed the animal and cell experiments. H.-Y.C., C.-H.C. and Y.I. performed the mitochondrial proteomics. H.J. and J.W. performed the experiments using β-less mice. K.T., K.I., H.-Y.C., T.Y., Y.O., Y.I. and S.K. analysed and interpreted the data. K.T. and S.K. wrote the manuscript. K.T., Y.I. and S.K. edited the manuscript.
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Supplementary Figs. 1–6 and Tables 4–6
Supplementary Table 1
List of the downregulated mitochondrial proteins in old mice.
Supplementary Table 2
List of the lipoic acid-interacting mitochondrial proteins in iBAT.
Supplementary Table 3
List of the downregulated mitochondrial proteins in adipo-Bola3 knockout mice.
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Tajima, K., Ikeda, K., Chang, HY. et al. Mitochondrial lipoylation integrates age-associated decline in brown fat thermogenesis. Nat Metab 1, 886–898 (2019). https://doi.org/10.1038/s42255-019-0106-z
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DOI: https://doi.org/10.1038/s42255-019-0106-z
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