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TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis

Author

Listed:
  • Donghua Hu

    (Washington University School of Medicine)

  • Min Tan

    (Washington University School of Medicine)

  • Dongliang Lu

    (Washington University School of Medicine)

  • Brian Kleiboeker

    (Washington University School of Medicine)

  • Xuejing Liu

    (Washington University School of Medicine)

  • Hongsuk Park

    (Washington University School of Medicine)

  • Alexxai V. Kravitz

    (Washington University School of Medicine)

  • Kooresh I. Shoghi

    (Washington University School of Medicine)

  • Yu-Hua Tseng

    (Joslin Diabetes Center, Harvard Medical School)

  • Babak Razani

    (Washington University School of Medicine
    University of Pittsburgh School of Medicine and UPMC)

  • Akihiro Ikeda

    (University of Wisconsin-Madison)

  • Irfan J. Lodhi

    (Washington University School of Medicine)

Abstract

Mitochondrial morphology, which is controlled by mitochondrial fission and fusion, is an important regulator of the thermogenic capacity of brown adipocytes. Adipose-specific peroxisome deficiency impairs thermogenesis by inhibiting cold-induced mitochondrial fission due to decreased mitochondrial membrane content of the peroxisome-derived lipids called plasmalogens. Here, we identify TMEM135 as a critical mediator of the peroxisomal regulation of mitochondrial fission and thermogenesis. Adipose-specific TMEM135 knockout in mice blocks mitochondrial fission, impairs thermogenesis, and increases diet-induced obesity and insulin resistance. Conversely, TMEM135 overexpression promotes mitochondrial division, counteracts obesity and insulin resistance, and rescues thermogenesis in peroxisome-deficient mice. Mechanistically, thermogenic stimuli promote association between peroxisomes and mitochondria and plasmalogen-dependent localization of TMEM135 in mitochondria, where it mediates PKA-dependent phosphorylation and mitochondrial retention of the fission factor Drp1. Together, these results reveal a previously unrecognized inter-organelle communication regulating mitochondrial fission and energy homeostasis and identify TMEM135 as a potential target for therapeutic activation of BAT.

Suggested Citation

  • Donghua Hu & Min Tan & Dongliang Lu & Brian Kleiboeker & Xuejing Liu & Hongsuk Park & Alexxai V. Kravitz & Kooresh I. Shoghi & Yu-Hua Tseng & Babak Razani & Akihiro Ikeda & Irfan J. Lodhi, 2023. "TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41849-8
    DOI: 10.1038/s41467-023-41849-8
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