Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.
Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141, Republic of Korea.
Nat Commun. 2023 Jun 23;14(1):3746. doi: 10.1038/s41467-023-39106-z.
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.
棕色脂肪组织（BAT）含有丰富的线粒体，具有通过解偶联呼吸产生热量的独特能力。在寒冷应激下，BAT 中的线粒体解偶联蛋白 1（UCP1）被激活，消耗电子传递链产生的线粒体质子动力势以产生热量。然而，其他在寒冷应激下棕色脂肪细胞呼吸和产热所需的线粒体因子在很大程度上尚不清楚。在这里，我们表明 LETM1 结构域包含蛋白 1（LETMD1）是一种 BAT 丰富且受冷诱导的蛋白，是冷刺激 BAT 呼吸和产热所必需的。邻近标记研究表明 LETMD1 是一种线粒体基质蛋白。Letmd1 敲除雄性小鼠表现出异常的 BAT 线粒体，并且在寒冷应激下无法进行适应性产热。Letmd1 敲除 BAT 中线粒体呼吸复合物蛋白的氧化磷酸化（OXPHOS）缺陷，呼吸受损。此外，BAT 特异性的 Letmd1 缺陷小鼠表现出与 Letmd1 敲除小鼠观察到的表型相同的表型。总之，我们证明了富含 BAT 的线粒体基质蛋白 LETMD1 发挥了组织自主性作用，对 BAT 线粒体功能和产热至关重要。
