Regulation of the ER-stress regulator IRE1α - a new approach to the modulation of ischemia-induced mitochondrial dysfunction and cell death

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Tissue damage due to ischemia reperfusion injury (IRI) remains a major cause of morbidity and mortality. While the tissue injury associated with IRI occurs primarily during reperfusion, different pathways triggered during ischemia prime the injury associated with reperfusion, including increased intracellular calcium flux and mitochondrial-stress associated cell death. Based on recently published data and preliminary work we propose that the endoplasmic reticulum (ER) associated homodimeric protein IRE1α acquires a transient monomeric state during the hypoxic phase, allowing heterodimerization with IP3R1. The IRE1α – IP3R1 heterodimer induces IP3R1 – VDAC1 channel formation at the ER-MAMs (ER-mitochondria associated membranes), which facilitates calcium flux from the ER to mitochondria. This calcium influx primes mitochondrial dysfunction and mitochondrial cell-death promoting effects during reperfusion. Based on further preliminary work we propose that this novel mechanism, which primes ischemic cells for damage, can be inhibited, thus preventing IRI-associated cell- and tissue damage. Among possible candidates regulating the IRE1α – IP3R1 heterodimer induced IP3R1-VDAC1 channel formation is activated protein C (aPC). aPC is a coagulation protease with cytoprotective effects, known to ameliorate IRI through poorly defined intracellular mechanisms. To investigate this novel mechanism and its regulation we wish to address the following aims: Aim-1: Investigate the functional relevance and molecular basis of the IRE1α–IP3R1 interaction; Aim-2: Identify the molecular pathways that regulate the new function of IRE1α at the ER-MAMs during IRI; Aim-3: Investigate the functional relevance and mechanistic interaction of aPC with IRE1α in IRI; We expect that answering these questions will enable us to design targeted approaches to specifically inhibit IRE1α – IP3R1 heterodimerization and thus preventing the mitochondrial calcium overload and mitochondrial dysfunction, which primes cells for damage. We thus expect new insights into mechanisms of ischemia-primed cell- and tissue-damage as well as into mechanisms regulating ER-MAM formation.