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 β₃ 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.

线粒体蛋白酶正在成为线粒体可塑性的关键调节剂，并通过执行高度调节的蛋白水解反应充当蛋白质质量监测和调节酶。然而，目前尚不清楚受调节的线粒体蛋白水解是否与细胞身份转换有机械联系。在这里，我们报告说，冷响应性线粒体蛋白水解是脂肪细胞生热重塑过程中白色至米色脂肪细胞命运编程的先决条件。产热刺激通过线粒体蛋白酶 LONP1 选择性促进成熟白色脂肪细胞中的线粒体蛋白质稳态。LONP1 依赖性蛋白水解的破坏会严重损害冷或 β ₃肾上腺素能激动剂诱导的成熟脂肪细胞从白色到米色的身份转换。从机制上讲，LONP1 选择性降解琥珀酸脱氢酶复合体铁硫亚基 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，从而实现脂肪细胞的细胞命运编程。最后，增强的 LONP1 表达可提高琥珀酸水平，并纠正与衰老相关的白色脂肪细胞向米色脂肪细胞转化和脂肪细胞生热能力的损伤。总之，这些发现表明 LONP1 将蛋白水解监视与线粒体代谢重连联系起来，并在脂肪细胞生热重塑过程中指导细胞身份转换。