ER- tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis

• 成果类型: Article
• 署名作者: Kim, Hyunbae; Chen, Qi; Ju, Donghong; Purandare, Neeraja; Chen, Xuequn; Samavati, Lobelia; Li, Li; Zhang, Ren; Grossman, Lawrence I.; Zhang, Kezhong
• 署名单位: Wayne State University; Wayne State University; Wayne State University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11311
• DOI: 10.1073/pnas.2410486121
• 发表日期: 2024-12-03
• 关键词: element-binding protein; fatty-acid oxidation; transcription factor; endoplasmic-reticulum; skeletal-muscle; upr; mechanisms

摘要

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 alpha (PPAR alpha), 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.