*4.3. UPR Regulation by MITOL*

In addition to the basic role of MITOL in unstressed conditions, recent evidence has implied that MITOL serves as a unique signaling regulator in several specific conditions. We recently identified a novel substrate, IRE1 α, for MITOL at the MCS between the ER and mitochondria [76]. IRE1 α is an ER membrane-integrated protein that possesses bifunctional activity as a kinase and endoribonuclease. The luminal domain of IRE1 α contributes to monitoring the stress level of the ER by sensing the emergence of unfolded proteins. Meanwhile, the cytosolic domain of IRE1 α, containing both catalytic domains, contributes to signal transduction from the ER to outside it in order to recover from ER damage during ER stress conditions. The ubiquitination of IRE1 α by MITOL determines the persistence of IRE1 α activation upon ER stress (Figure 4B). MITOL-catalyzed ubiquitination of IRE1 α is accompanied by binding to the mediator BIM for a smaller state of (or less stable) IRE1 α oligomerization, allowing the catalytic activation of IRE1 α only for the short term. This regulation of IRE1 α is pivotal with regard to termination of the UPR after the recovery of ER homeostasis. Unresolved IRE1 α activation indeed triggers an alternative outcome of IRE1 α signaling, namely, cell death. Importantly, severe ER stress attenuates the ubiquitination levels of IRE1 α by MITOL via unclear mechanisms. Therefore, the unlimited IRE1 α oligomerization and activation promote the induction of cell death during severe and irremediable ER stress. Taking these findings together, MITOL prevents the signal switching of IRE1 α from cell survival to cell death via direct ubiquitination of IRE1 α at the MCS between the ER and mitochondria. The ER network accumulates severe abnormalities, both functional and morphological, during irremediable ER stress. Thus, it might be reasonable to set the monitoring system, related to the signal switch of the UPR, outside the ER, such as on the mitochondrial surface. Several mitochondrial molecules therefore hold therapeutic potential in diseases initiated or aggravated by ER stress, not only mitochondrial stress.
