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Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice.

Anna ParkKwang-Eun KimIsaac ParkSang Heon LeeKun-Young ParkMinkyo JungXiaoxu LiMaroun Bou SleimanSu Jeong LeeDae-Soo KimJaehoon KimDae-Sik LimEui-Jeon WooEun Woo LeeBaek Soo HanKyoung-Jin OhSang Chul LeeJohan AuwerxJi Young MunHyun-Woo RheeWon Kon KimKwang-Hee BaeJae Myoung Suh
Published in: Nature communications (2023)
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.
Keyphrases
  • adipose tissue
  • oxidative stress
  • insulin resistance
  • binding protein
  • amino acid
  • type diabetes
  • heat stress
  • high fat diet
  • diabetic rats
  • dna methylation
  • genome wide
  • reactive oxygen species
  • single cell
  • protein kinase