Coordinated regulation of the metaboproteome by Hsp90 chaperones controls metabolic plasticity

Heat shock protein 90 (Hsp90) chaperones participate in the stabilization and activation of hundreds of proteins, thereby acting as signaling hubs. A mitochondrial subpopulation of Hsp90 has been previously described; however, little is known about its role in metabolism. Here, we showed that loss of individual Hsp90 isoforms differentially affects oxygen consumption and metabolic flexibility. Proteomic and metabolomic evaluation demonstrated that Hsp90 regulates the mitochondrial metabolic network, including respiration, fatty acid oxidation, and redox homeostasis. Loss of the mitochondrial chaperone TRAP1 induced compensatory binding of Hsp90s to TRAP1-dependent proteins, indicating a mechanism for the role of Hsp90 chaperones in metabolic reprogramming. When considered with previous findings, a temporal pattern of regulation emerges whereby Hsp90s control the transcription, translation, import, and assembly of mitochondrial protein complexes. Our findings expand the scope of Hsp90-regulated processes and potentially inform the effects of isoform-specific Hsp90 inhibitors on metabolic reprogramming in cancer and other diseases.

热休克蛋白90（Hsp90）分子伴侣参与数百种蛋白质的稳定与激活，因此可作为信号枢纽发挥功能。此前已有研究报道了定位于线粒体的Hsp90亚群，但学界对其在代谢过程中的功能尚知之甚少。本研究发现，单一Hsp90亚型的缺失会对细胞耗氧率与代谢灵活性产生差异性影响。蛋白质组学与代谢组学分析表明，Hsp90可调控线粒体代谢网络，涵盖呼吸作用、脂肪酸氧化及氧化还原稳态等过程。线粒体分子伴侣TRAP1的缺失会诱导Hsp90与TRAP1依赖型蛋白质产生代偿性结合，这揭示了Hsp90分子伴侣介导代谢重编程的潜在机制。结合既往研究结果，可推导出一套时序调控模式：Hsp90可通过调控线粒体蛋白质复合物的转录、翻译、导入与组装过程发挥功能。本研究成果拓展了Hsp90所调控的生物学过程范畴，同时可为靶向特定亚型的Hsp90抑制剂在癌症及其他疾病中对代谢重编程的影响提供理论参考。