| Mechanisms by which NADPH could affect ER function. NADPH is a major factor in redox homeostasis. In both the cytosol and mitochondria, NADPH is used by glutathione reductase (GR) and thioredoxin reductase (TrxR). Generation of GSH by GR in either compartment could move into the ER and alter the oxidizing environment by interacting with PDI family members for disulfide reduction, whether during isomerization or for retrotranslocation. Similarly, TrxR has the potential to transfer electrons across the ER membrane-by a currently unknown mechanism-for reduction of non-native disulfides during isomerization. Reduction by ERdj5 is also required for protein retrotranslocation during ERAD. GSH and electrons entering via the Trx pathway may also influence ER calcium by regulating SERCA. SERCA is activated by reduction (ERdj5) and inactivated by oxidation (ERp57 and TMX1), and is also activated by S-glutathionylation, providing a direct role for glutathione in calcium homeostasis. Finally, NADPH oxidase 4 (NOX4) uses cytosolic NADPH to generate H 2 O 2 in the ER lumen. This H 2 O 2 could be used by ER-resident PRDX4 and GPx7/8 during PDI reoxidation as shown in Figure 1. The H 2 O 2 produced by NOX4 also has the potential to regulate SERCA redox and calcium homeostasis. Though the NADPH pool in the ER lumen appears uncoupled from the protein folding machinery, it nonetheless plays a role in overall redox and regulates steroid activation by 11β-hydroxysteroid dehydrogenase (11β-HSD). Whether there are reductases that use NADPH in the ER lumen remains unknown, and thus a role for NADPH in protein folding cannot be fully excluded.

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... we recently showed that NADPH generated by the TCA cycle leads to a hypo-oxidizing ER and, surprisingly, increased sensitivity to ER stress ( Gansemer et al., 2020). In this section, we will describe three major pathways by which NADPH levels can be transmitted to the ER lumen ( Figure 3). As will be discussed, glutathione is one possible candidate because it relies on NADPH for reduction, which is thought to occur in the mitochondria and cytosol, but not the ER (Lu, 2013;Ribas et al., 2014;Couto et al., 2016), and a potential mechanism for the entry of reduced glutathione into the ER has been characterized in yeast ( Ponsero et al., 2017). ...