CREBH Regulates Mitochondrial Unfolded Protein Response to Maintain Energy Homeostasis

The Mitochondrial Unfolded Protein Response (UPRmt), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPRmt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPRmt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor (PPAR), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPRmt transcriptional regulators, independent of the ER-originated UPR (UPRER) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPRmt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.线粒体未折叠蛋白反应（Mitochondrial Unfolded Protein Response, UPRmt）是起源于线粒体的、针对线粒体蛋白质稳态失衡的应激反应，广泛参与多种病理生理过程。本研究揭示，内质网（ER）锚定的应激传感器CREBH可调控UPRmt，以维持肝脏的线粒体稳态与功能。CREBH在能量需求诱导的肝脏线粒体相关膜（MAM）扩张中富集，且是该过程所必需的。在禁食应激或昼夜节律周期中，CREBH被激活，促进肝脏中编码UPRmt关键酶、分子伴侣及调控因子的基因表达。活化的CREBH与过氧化物酶体增殖物激活受体（PPAR）协同，独立于内质网未折叠蛋白反应（UPRER）通路，激活两种主要的UPRmt转录调控因子——激活转录因子（ATF）5与ATF4的表达。肝脏CREBH缺失会导致线粒体未折叠蛋白蓄积、线粒体膜电位降低以及细胞氧化还原状态异常升高。CREBH缺失引发的线粒体功能失调，伴随肝脏线粒体氧化磷酸化（OXPHOS）增强而糖酵解水平降低。CREBH敲除小鼠表现出脂肪酸氧化缺陷，且能量产生更依赖碳水化合物氧化。综上，本研究阐明，在生理应激条件下，肝脏UPRmt通过CREBH通路激活，揭示了内质网与线粒体之间在应激状态下维持线粒体蛋白质稳态与能量稳态的分子联系。