Abstract: SA-PO0145
Renalase Activates Mitochondrial Leak Metabolism to Repair Mitochondrial Damage and Promote Cell Survival
Session Information
- AKI: Mechanisms - 3
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Guo, Xiaojia, Yale School of Medicine, New Haven, Connecticut, United States
- Chen, Rongmin, Yale School of Medicine, New Haven, Connecticut, United States
- Shugrue, Christine, Yale School of Medicine, New Haven, Connecticut, United States
- Chen, Tian-Min, Yale School of Medicine, New Haven, Connecticut, United States
- M'Saad, Ons, Panluminate, New Haven, Connecticut, United States
- Tian, Yuan, Yale School of Medicine, New Haven, Connecticut, United States
- Gorelick, Fred, Yale School of Medicine, New Haven, Connecticut, United States
- Bewersdorf, Joerg, Yale School of Medicine, New Haven, Connecticut, United States
- Safirstein, Robert L., Yale School of Medicine, New Haven, Connecticut, United States
- Jonas, Elizabeth A., Yale School of Medicine, New Haven, Connecticut, United States
- Desir, Gary V., Yale School of Medicine, New Haven, Connecticut, United States
Background
A variety of mechanisms can enhance cell survival. Here, we describe a new regulated role for mitochondrial metabolism in cellular stress response and repair. Renalase (RNLS) is a flavin-dependent NADH oxidase. It interacts with its receptor, ATP2b4, upon secretion, activates intracellular signaling, and promotes cell survival. Deletion of RNLS potentiates acute organ injury, while administration of exogenous RNLS reduces it. We now explore the mechanism of this effect.
Methods
Mitochondria from WT or KO mouse kidneys were tested for complexes I and II activity. WT and RNLS KO Renal cells were compared for their oxygen consumption rate using Seahorse XF technology. Puromycin labeling of mouse proximal tubule TKPTS cells was used to study protein synthesis. Mass spec and immunoblotting were used to identify protein and protein expression differences. Protein interaction was studied with Proximity Ligation Assay. Kidney injury was introduced to WT and KO mice with 15mg/kg cisplatin. Mitochondrial morphology was studied using electron microscopy.
Results
Extracellular RNLS causes a selective, sustained, time-dependent increase in cellular protein synthesis without affecting cell proliferation. Functional analysis of newly and differentially abundant proteins over 24 hours reveals changes in one-carbon metabolism and ribosomal biogenesis pathways at one hour. This precedes the increase in protein synthesis. We find a pool of intracellular RNLS in the mitochondrial matrix where it binds directly to the ATP synthase alpha and beta subunits (ATP5α and ATP5β), can open the ATP synthase c-subunit leak channel, and induce mitochondrial leak. Inhibition of RNLS signaling or the mitochondrial leak significantly decreases RNLS-mediated protein synthesis. The genetic deletion of RNLS (RNLS KO) reduces complex I and II activities. Mitochondrial injury is more severe in the RNLS KO kidney after acute stress. It is characterized by decreased protein synthesis and increased mitophagy, as evidenced by low PGC1α and increased AMPKα and Parkin.
Conclusion
This study highlights a fundamental role for RNLS in activating mitochondrial leak metabolism to induce a rapid onset of protein synthesis, underscoring its protective properties.
Funding
- Other NIH Support