Inhibiting nutrient catabolism alleviates ER stress in metabolically active cells NADPH production and glutathione redox link TCA activity to ER homeostasis ER client protein oxidation, maturation, and ERAD respond to metabolic activity Cells lacking the Mitochondrial Pyruvate Carrier are resistant to ER stress

Summary The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation are unclear, including which pathways contribute to the phenotype in each organ. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver, but not the kidney; while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress.

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1 2 Endoplasmic reticulum (ER) stress is associated with dysregulated metabolism, but little is 3 known about how the ER responds to metabolic activity. Here, working primarily in mouse 4 hepatocytes, we show that decreasing the availability of substrate for the TCA cycle diminished 5 NADPH production and attenuated ER stress in a manner that depended on glutathione 6 oxidation. ER stress was also alleviated by impairing either TCA-dependent NADPH production 7 or Glutathione Reductase. Conversely, stimulating TCA activity favored NADPH production, 8 glutathione reduction, and ER stress. Validating these findings, we show that deletion of the 9 mitochondrial pyruvate carrier, which is known to decrease TCA cycle activity and protect the 10 liver from diet-induced injury, also diminished NADPH, elevated glutathione oxidation, and 11 alleviated ER stress. These results provide independent genetic evidence that mitochondrial 12 oxidative metabolism is linked to ER homeostasis. Our results demonstrate a novel pathway of 13 communication between mitochondria and the ER, through relay of redox metabolites. 14 15 16