State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing University, Nanjing, China.
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Nat Cell Biol. 2023 Jun;25(6):848-864. doi: 10.1038/s41556-023-01155-3. Epub 2023 May 22.
Mitochondrial proteases are emerging as key regulators of mitochondrial plasticity and acting as both protein quality surveillance and regulatory enzymes by performing highly regulated proteolytic reactions. However, it remains unclear whether the regulated mitochondrial proteolysis is mechanistically linked to cell identity switching. Here we report that cold-responsive mitochondrial proteolysis is a prerequisite for white-to-beige adipocyte cell fate programming during adipocyte thermogenic remodelling. Thermogenic stimulation selectively promotes mitochondrial proteostasis in mature white adipocytes via the mitochondrial protease LONP1. Disruption of LONP1-dependent proteolysis substantially impairs cold- or β adrenergic agonist-induced white-to-beige identity switching of mature adipocytes. Mechanistically, LONP1 selectively degrades succinate dehydrogenase complex iron sulfur subunit B and ensures adequate intracellular succinate levels. This alters the histone methylation status on thermogenic genes and thereby enables adipocyte cell fate programming. Finally, augmented LONP1 expression raises succinate levels and corrects ageing-related impairments in white-to-beige adipocyte conversion and adipocyte thermogenic capacity. Together, these findings reveal that LONP1 links proteolytic surveillance to mitochondrial metabolic rewiring and directs cell identity conversion during adipocyte thermogenic remodelling.
线粒体蛋白酶作为线粒体可塑性的关键调节因子而出现，它们通过执行高度调控的蛋白水解反应，既是蛋白质质量监控酶，也是调节酶。然而，调控性的线粒体蛋白水解是否与细胞身份转换在机制上有关，目前仍不清楚。在这里，我们报告冷响应性线粒体蛋白水解是脂肪细胞产热重塑过程中白色脂肪细胞向米色脂肪细胞命运编程的必要条件。通过线粒体蛋白酶 LONP1，热刺激选择性地促进成熟白色脂肪细胞中线粒体蛋白稳态。破坏 LONP1 依赖性蛋白水解会严重损害成熟脂肪细胞中冷或β肾上腺素激动剂诱导的白色向米色身份转换。在机制上，LONP1 选择性地降解琥珀酸脱氢酶复合物铁硫亚基 B，并确保足够的细胞内琥珀酸水平。这改变了产热基因上的组蛋白甲基化状态，从而使脂肪细胞的命运编程成为可能。最后，增强 LONP1 的表达会提高琥珀酸水平，并纠正与衰老相关的白色向米色脂肪细胞转化和脂肪细胞产热能力的损伤。总之，这些发现表明 LONP1 将蛋白水解监控与线粒体代谢重编程联系起来，并在脂肪细胞产热重塑过程中指导细胞身份转换。
