Abstract: FR-PO0356
IRE1α Drives Renal Ischemia-Reperfusion Injury by Directly Sensing Adenosine Triphosphate (ATP) Levels and Promoting Mitochondrial Calcium Loading at Endoplasmic Reticulum-Mitochondrial Associated Membranes (ER-MAMs)
Session Information
- AKI: Mechanisms - Metabolism and Repair
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Mathew, Akash, Universitat Leipzig, Leipzig, SN, Germany
- Isermann, Berend Heinrich, Universitat Leipzig, Leipzig, SN, Germany
Background
Mitochondrial calcium loading, excessive ROS generation, cell death, and tissue injury are hallmarks of ischemia reperfusion injury (IRI). Experiments have addressed these aspects individually, providing some mechanistic insights. However, overall, our insights into mechanisms leading to IRI are limited and we lack in particular druggable targets. Considering that both the endoplasmic reticulum and mitochondria regulate cell survival and death and their interaction we evaluate in this project the role of the ER stress sensor IRE1alpha in IRI.
Methods
We employed CRISPR-Cas9 to knock out (KO) IRE1alpha in immortalized murine tubular proximal cells. For functional studies, we generated various IRE1alpha mutants which were re-expressed in IRE1alpha KO cells. We also generated inducible whole body or endothelial- or tubular-cell specific IRE1 alpha KO mice to evaluate the role of IRE1alpha in ischemic injury models such as stroke, kidney ischemia reperfusion injury, and cold ischemic injury associated organ transplantation. To gain mechanistic insights we additionally employed calcium imaging, co-immunoprecipitation, proximity ligation assay, several proteomic studies, and cell free experiments.
Results
IRE1alpha drives mitochondrial calcium loading and cell death during ischemia. Mitochondrial calcium accumulation primes mitochondria for a 'burst' of activity during the initial phase of reperfusion injury when oxygen and glucose are re-introduced. These activities of IRE1alpha are independent of its canonical signalling. Rather, IRE1alpha directly senses intracellular ATP/ADP levels, inducing mitochondrial calcium accumulation at low ATP levels during ischemia. KO of IRE1alpha or mimicking ATP-binding to IRE1alpha prevents ischemic cell injury and cell death.
Conclusion
Our data identify IRE1alpha as a central inducer of ischemia-induced injury through mitochondrial calcium loading via IP3R1-VDAC1 at ER-MAMs. These data are in agreement with a model in which cells stressed by ischemia attempt to adapt to the low energy state by calcium loading through IRE1alpha aiming to sustain mitochondrial energy generation. However, excessive calcium loading primes cells for death. Targeting ATP-sensing by IRE1alpha may allow to modulate this pathway and thus to potentially suppress ischemic tissue injury.
Acknowledgment
This work was supported by the following grants: Deutsche Forschungsgemeinschaft (IS-67/22-1, IS-67/25-1, IS-67/26-1, IS-67/29-1, 361210922/GRK2408/P7&P9 to BI, CRC1423, project C07 to B. Isermann) and from the ERC (101141561 TameThiflam) to B. Isermann.
Funding
- Government Support – Non-U.S.