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

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 m...

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Autores principales: Hu, Donghua, Tan, Min, Lu, Dongliang, Kleiboeker, Brian, Liu, Xuejing, Park, Hongsuk, Kravitz, Alexxai V., Shoghi, Kooresh I., Tseng, Yu-Hua, Razani, Babak, Ikeda, Akihiro, Lodhi, Irfan J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541902/
https://www.ncbi.nlm.nih.gov/pubmed/37773161
http://dx.doi.org/10.1038/s41467-023-41849-8
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author Hu, Donghua
Tan, Min
Lu, Dongliang
Kleiboeker, Brian
Liu, Xuejing
Park, Hongsuk
Kravitz, Alexxai V.
Shoghi, Kooresh I.
Tseng, Yu-Hua
Razani, Babak
Ikeda, Akihiro
Lodhi, Irfan J.
author_facet Hu, Donghua
Tan, Min
Lu, Dongliang
Kleiboeker, Brian
Liu, Xuejing
Park, Hongsuk
Kravitz, Alexxai V.
Shoghi, Kooresh I.
Tseng, Yu-Hua
Razani, Babak
Ikeda, Akihiro
Lodhi, Irfan J.
author_sort Hu, Donghua
collection PubMed
description 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.
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spelling pubmed-105419022023-10-02 TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis Hu, Donghua Tan, Min Lu, Dongliang Kleiboeker, Brian Liu, Xuejing Park, Hongsuk Kravitz, Alexxai V. Shoghi, Kooresh I. Tseng, Yu-Hua Razani, Babak Ikeda, Akihiro Lodhi, Irfan J. Nat Commun Article 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. Nature Publishing Group UK 2023-09-29 /pmc/articles/PMC10541902/ /pubmed/37773161 http://dx.doi.org/10.1038/s41467-023-41849-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Hu, Donghua
Tan, Min
Lu, Dongliang
Kleiboeker, Brian
Liu, Xuejing
Park, Hongsuk
Kravitz, Alexxai V.
Shoghi, Kooresh I.
Tseng, Yu-Hua
Razani, Babak
Ikeda, Akihiro
Lodhi, Irfan J.
TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis
title TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis
title_full TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis
title_fullStr TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis
title_full_unstemmed TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis
title_short TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis
title_sort tmem135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541902/
https://www.ncbi.nlm.nih.gov/pubmed/37773161
http://dx.doi.org/10.1038/s41467-023-41849-8
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