2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction

Mitochondria play a crucial role in regulating cellular homeostasis in response to intrinsic and extrinsic cues by changing cellular metabolism to meet these challenges.However, the molecular underpinnings of this regulation and the complete spectrum of these physiological outcomes remain largely unexplored. In this study, we elucidate the mechanisms driving the whitening phenotype in brown adipose tissue (BAT) deficient in the mitochondrial matrix protease CLPP. We find that CLPP-deficient BAT shows aberrant accumulation of lipid droplets, which occurs independently of defects in oxygen consumption and fatty acid oxidation. Our results indicate that mitochondrial dysfunction due to CLPP deficiency leads to the build-up of the oncometabolite 2-hydroxyglutarate (2-HG), which in turn promotes lipid droplet enlargement. We further demonstrate that 2-HG influences gene expression and decreases nuclear stiffness by modifying epigenetic signatures. We propose that lipid accumulation and altered nuclear stiffness regulated through 2-HG are novel stress responses to mitochondrial dysfunction.线粒体通过重塑细胞代谢以适配内外部信号刺激，在调控细胞稳态以应对各类应激挑战中发挥关键作用。然而，该调控过程的分子基础以及这类生理效应的完整谱式，目前仍未得到充分探索。本研究针对线粒体基质蛋白酶CLPP缺陷的棕色脂肪组织（BAT），阐明了驱动其变白表型的分子机制。研究发现，CLPP缺陷的BAT存在脂滴异常蓄积，且该现象与氧耗缺陷及脂肪酸氧化障碍无关。本研究结果显示，CLPP缺陷引发的线粒体功能障碍，会导致肿瘤代谢物2-羟基戊二酸（2-hydroxyglutarate, 2-HG）蓄积，进而促进脂滴增大。本研究进一步证实，2-HG可通过修饰表观遗传标记，调控基因表达并降低细胞核刚度。本研究提出，经2-HG调控的脂滴蓄积与细胞核刚度改变，是线粒体功能障碍引发的新型应激反应。