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

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 and Irfan J. Lodhi ()
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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
Akihiro Ikeda: University of Wisconsin-Madison
Irfan J. Lodhi: Washington University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41849-8

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