Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice
Abstract Brown adipose tissue (BAT) has abundant mitochondria with the unique capability of generating heat via uncoupled respiration. Mitochondrial uncoupling protein 1 (UCP1) is activated in BAT during cold stress and dissipates mitochondrial proton motive force generated by the electron transport...
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Nature Portfolio
2023-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39106-z |
| _version_ | 1797795591637434368 |
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| author | Anna Park Kwang-eun Kim Isaac Park Sang Heon Lee Kun-Young Park Minkyo Jung Xiaoxu Li Maroun Bou Sleiman Su Jeong Lee Dae-Soo Kim Jaehoon Kim Dae-Sik Lim Eui-Jeon Woo Eun Woo Lee Baek Soo Han Kyoung-Jin Oh Sang Chul Lee Johan Auwerx Ji Young Mun Hyun-Woo Rhee Won Kon Kim Kwang-Hee Bae Jae Myoung Suh |
| author_facet | Anna Park Kwang-eun Kim Isaac Park Sang Heon Lee Kun-Young Park Minkyo Jung Xiaoxu Li Maroun Bou Sleiman Su Jeong Lee Dae-Soo Kim Jaehoon Kim Dae-Sik Lim Eui-Jeon Woo Eun Woo Lee Baek Soo Han Kyoung-Jin Oh Sang Chul Lee Johan Auwerx Ji Young Mun Hyun-Woo Rhee Won Kon Kim Kwang-Hee Bae Jae Myoung Suh |
| author_sort | Anna Park |
| collection | DOAJ |
| description | Abstract Brown adipose tissue (BAT) has abundant mitochondria with the unique capability of generating heat via uncoupled respiration. Mitochondrial uncoupling protein 1 (UCP1) is activated in BAT during cold stress and dissipates mitochondrial proton motive force generated by the electron transport chain to generate heat. However, other mitochondrial factors required for brown adipocyte respiration and thermogenesis under cold stress are largely unknown. Here, we show LETM1 domain-containing protein 1 (LETMD1) is a BAT-enriched and cold-induced protein required for cold-stimulated respiration and thermogenesis of BAT. Proximity labeling studies reveal that LETMD1 is a mitochondrial matrix protein. Letmd1 knockout male mice display aberrant BAT mitochondria and fail to carry out adaptive thermogenesis under cold stress. Letmd1 knockout BAT is deficient in oxidative phosphorylation (OXPHOS) complex proteins and has impaired mitochondrial respiration. In addition, BAT-specific Letmd1 deficient mice exhibit phenotypes identical to those observed in Letmd1 knockout mice. Collectively, we demonstrate that the BAT-enriched mitochondrial matrix protein LETMD1 plays a tissue-autonomous role that is essential for BAT mitochondrial function and thermogenesis. |
| first_indexed | 2024-03-13T03:20:17Z |
| format | Article |
| id | doaj.art-8abfab449c994b11bb6233d6bda9aba7 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T03:20:17Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-8abfab449c994b11bb6233d6bda9aba72023-06-25T11:22:22ZengNature PortfolioNature Communications2041-17232023-06-0114111410.1038/s41467-023-39106-zMitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male miceAnna Park0Kwang-eun Kim1Isaac Park2Sang Heon Lee3Kun-Young Park4Minkyo Jung5Xiaoxu Li6Maroun Bou Sleiman7Su Jeong Lee8Dae-Soo Kim9Jaehoon Kim10Dae-Sik Lim11Eui-Jeon Woo12Eun Woo Lee13Baek Soo Han14Kyoung-Jin Oh15Sang Chul Lee16Johan Auwerx17Ji Young Mun18Hyun-Woo Rhee19Won Kon Kim20Kwang-Hee Bae21Jae Myoung Suh22Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Graduate School of Medical Science and Engineering, KAISTDepartment of Chemistry, Seoul National UniversityGraduate School of Medical Science and Engineering, KAISTGraduate School of Medical Science and Engineering, KAISTNeural Circuit Research Group, Korea Brain Research InstituteLaboratory of Integrative Systems Physiology, École polytechnique fédérale de Lausanne (EPFL)Laboratory of Integrative Systems Physiology, École polytechnique fédérale de Lausanne (EPFL)Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST)Department of Biological Sciences, KAISTNational Creative Research Center for Cell Plasticity, KAIST Stem Cell Center, Department of Biological Sciences, KAISTDepartment of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST)Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST)Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Laboratory of Integrative Systems Physiology, École polytechnique fédérale de Lausanne (EPFL)Neural Circuit Research Group, Korea Brain Research InstituteDepartment of Chemistry, Seoul National UniversityMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Graduate School of Medical Science and Engineering, KAISTAbstract Brown adipose tissue (BAT) has abundant mitochondria with the unique capability of generating heat via uncoupled respiration. Mitochondrial uncoupling protein 1 (UCP1) is activated in BAT during cold stress and dissipates mitochondrial proton motive force generated by the electron transport chain to generate heat. However, other mitochondrial factors required for brown adipocyte respiration and thermogenesis under cold stress are largely unknown. Here, we show LETM1 domain-containing protein 1 (LETMD1) is a BAT-enriched and cold-induced protein required for cold-stimulated respiration and thermogenesis of BAT. Proximity labeling studies reveal that LETMD1 is a mitochondrial matrix protein. Letmd1 knockout male mice display aberrant BAT mitochondria and fail to carry out adaptive thermogenesis under cold stress. Letmd1 knockout BAT is deficient in oxidative phosphorylation (OXPHOS) complex proteins and has impaired mitochondrial respiration. In addition, BAT-specific Letmd1 deficient mice exhibit phenotypes identical to those observed in Letmd1 knockout mice. Collectively, we demonstrate that the BAT-enriched mitochondrial matrix protein LETMD1 plays a tissue-autonomous role that is essential for BAT mitochondrial function and thermogenesis.https://doi.org/10.1038/s41467-023-39106-z |
| spellingShingle | Anna Park Kwang-eun Kim Isaac Park Sang Heon Lee Kun-Young Park Minkyo Jung Xiaoxu Li Maroun Bou Sleiman Su Jeong Lee Dae-Soo Kim Jaehoon Kim Dae-Sik Lim Eui-Jeon Woo Eun Woo Lee Baek Soo Han Kyoung-Jin Oh Sang Chul Lee Johan Auwerx Ji Young Mun Hyun-Woo Rhee Won Kon Kim Kwang-Hee Bae Jae Myoung Suh Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice Nature Communications |
| title | Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice |
| title_full | Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice |
| title_fullStr | Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice |
| title_full_unstemmed | Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice |
| title_short | Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice |
| title_sort | mitochondrial matrix protein letmd1 maintains thermogenic capacity of brown adipose tissue in male mice |
| url | https://doi.org/10.1038/s41467-023-39106-z |
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