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Mitochondrial lipoylation integrates age-associated decline in brown fat thermogenesis

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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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Fig. 1: Age-associated decline in BAT thermogenesis is coupled with a post-transcriptional impairment in the mitochondrial fuel oxidation pathway.
Fig. 2: Reduced mitochondrial lipoylation and iron–sulfur cluster formation in aged BAT.
Fig. 3: A requirement of mitochondrial lipoylation for fuel use and thermogenesis in BAT.
Fig. 4: Mitochondrial lipoylation in BAT is required for whole-body energy homoeostasis and glucose metabolism.
Fig. 5: Age-dependent effects of α-lipoic acid supplementation in mice and humans.
Fig. 6: Enhanced mitochondrial lipoylation by α-lipoic acid supplementation restores BAT activity in aged mice via the BOLA3 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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Author notes

  1. Kenji Ikeda

    Present address: Department of Molecular Endocrionology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan

  2. Hsin-Yi Chang

    Present address: Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan

Authors and Affiliations

  1. University of California, San Francisco Diabetes Center, San Francisco, CA, USA

    Kazuki Tajima, Kenji Ikeda, Takeshi Yoneshiro, Yasuo Oguri & Shingo Kajimura

  2. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA, USA

    Kazuki Tajima, Kenji Ikeda, Takeshi Yoneshiro, Yasuo Oguri & Shingo Kajimura

  3. Department of Cell and Tissue Biology, University of California, San Francisco, CA, USA

    Kazuki Tajima, Kenji Ikeda, Takeshi Yoneshiro, Yasuo Oguri & Shingo Kajimura

  4. Department of Molecular and Cellular Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    Hsin-Yi Chang, Chih-Hsiang Chang & Yasushi Ishihama

  5. Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA

    Heejin Jun & Jun Wu

  6. Department of Molecular & Integrative Physiology, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA

    Jun Wu

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Contributions

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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Correspondence to Shingo Kajimura.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–6 and Tables 4–6

Reporting Summary

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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