Crosstalk and barriers between the electron carriers of the endoplasmic reticulum.

SIGNIFICANCE: The lumen of the endoplasmic reticulum (ER) constitutes a separate compartment with a special proteome and metabolome. The characteristic redox environment required for the optimal functioning of local pathways is defined by the redox couples of the main electron carriers. These molecules, glutathione, pyridine nucleotides, and ascorbic acid, are present within the ER, but their composition, concentration, and redox state are characteristically different from those observed in other subcellular compartments. Spatial and kinetic barriers contribute to the generation and maintenance of this special redox environment. RECENT ADVANCES: The ER redox has usually been considered from the perspective of oxidative protein folding, one of the major functions of the ER. Thus, the lumen has been described as a relatively oxidizing subcellular compartment. CRITICAL ISSUES: The ER redoxome has been scantily mapped. However, recent observations suggest that the redox systems in reduced and oxidized states are present simultaneously. The concerted actions of transmembrane uptake processes and local oxidoreductases as well as the absence of specific transport and enzyme activities maintain the oxidized state of the thiol-disulfide systems and the reduced state of the pyridine nucleotide redox systems. These states are prerequisites for the normal redox reactions localized in the ER. FUTURE DIRECTIONS: An outline of the interactions between the major electron carriers of the ER will contribute to a better understanding of human diseases related to ER redox homeostasis.