[Title]
Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice

[Author] 
Anna Park1,14, Kwang-eun Kim2,3,14, Isaac Park3 , Sang Heon Lee2 , Kun-Young Park 2 , Minkyo Jung4 , Xiaoxu Li5 , Maroun Bou Sleiman 5 , Su Jeong Lee1,6, Dae-Soo Kim 6,7, Jaehoon Kim8 , Dae-Sik Lim 9 , Eui-Jeon Woo 6,10, Eun Woo Lee 1,6, Baek Soo Han6,11, Kyoung-Jin Oh 1,6, Sang Chul Lee1 , Johan Auwerx 5 , Ji Young Mun4 , Hyun-Woo Rhee 3 , Won Kon Kim 1,6,12 , Kwang-Hee Bae 1,13 & Jae Myoung Suh 2

1 Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
2 Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea.
3 Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea.
4 Neural Circuit Research Group, Korea Brain Research Institute, Daegu 41068, Republic of Korea.
5 Laboratory of Integrative Systems Physiology, École polytechnique fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
6 Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Republic of Korea.
7 Digital Biotech Innovation Center, KRIBB, Daejeon 34141, Republic of Korea.
8 Department of Biological Sciences, KAIST, Daejeon 34141, Republic of Korea.
9 National Creative Research Center for Cell Plasticity, KAIST Stem Cell Center, Department of Biological Sciences, KAIST, Daejeon 34141, Republic of Korea.
10 Disease Target Structure Research Center, KRIBB, Daejeon 34141, Republic of Korea.
11 Biodefense Research Center, KRIBB, Daejeon 34141, Republic of Korea.
12 School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea.
13 Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, CA 92697, USA.
14 These authors contributed equally: Anna Park, Kwang-eun Kim.

[Journal] 
Nature Communications volume 14, Article number: 3746 (2023) 

[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.