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Updated: Sep 6, 2025
Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration
Published on: June 7, 2014
RIP3 Translocation into Mitochondria Promotes Mitofilin Degradation to Increase Inflammation and Kidney Injury after
Yansheng Feng1, Abdulhafiz Imam Aliagan1, Nathalie Tombo1
1Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Abstract:
The receptor-interacting protein kinase 3 (RIP3) has been reported to regulate programmed necrosis-necroptosis forms of cell death with important functions in inflammation. We investigated whether RIP3 translocates into mitochondria in response to renal ischemia-reperfusion (I/R) to interact with inner mitochondrial protein (Mitofilin) and promote mtDNA release into the cytosol. We found that release of mtDNA activates the cGAS-STING pathway, leading to increased nuclear transcription of pro-inflammatory markers that exacerbate renal I/R injury. Monolateral C57/6N and RIP3-/- mice kidneys were subjected to 60 min of ischemia followed by either 12, 24, or 48 h of reperfusion. In WT mice, we found that renal I/R injury increased RIP3 levels, as well as its translocation into mitochondria. We observed that RIP3 interacts with Mitofilin, likely promoting its degradation, resulting in increased mitochondria damage and mtDNA release, activation of the cGAS-STING-p65 pathway, and increased transcription of pro-inflammatory markers. All of these effects observed in WT mice were decreased in RIP3-/- mice. In HK-2, RIP3 overexpression or Mitofilin knockdown increased cell death by activating the cGAS-STING-p65 pathway. Together, this study point to an important role of the RIP3-Mitofilin axis in the initiation and development of renal I/R injury.
Insights
Receptor-interacting protein kinase 3 (RIP3) moves into mitochondria during kidney injury, interacting with Mitofilin to cause cell death and inflammation via the cGAS-STING pathway.
Area of Science:
- Cell Biology
- Immunology
- Renal Pathophysiology
Background:
- Receptor-interacting protein kinase 3 (RIP3) regulates necroptosis, a form of programmed cell death.
- Inflammation plays a critical role in renal ischemia-reperfusion (I/R) injury.
Purpose of the Study:
- To investigate RIP3 translocation into mitochondria during renal I/R injury.
- To determine if RIP3 interacts with Mitofilin and promotes mitochondrial damage and mtDNA release.
- To elucidate the role of the RIP3-Mitofilin axis in activating the cGAS-STING pathway and exacerbating renal I/R injury.
Main Methods:
- Utilized unilateral C57/6N and RIP3 knockout mice subjected to renal ischemia-reperfusion.
- Analyzed RIP3 levels and mitochondrial translocation post-I/R.
- Investigated RIP3-Mitofilin interaction, mtDNA release, and cGAS-STING pathway activation.
- Employed HK-2 cells to study RIP3 overexpression and Mitofilin knockdown effects.
Main Results:
- Renal I/R increased RIP3 levels and its translocation into mitochondria in wild-type mice.
- RIP3 interacted with Mitofilin, leading to its degradation, mitochondrial damage, and mtDNA release.
- mtDNA release activated the cGAS-STING-p65 pathway, increasing pro-inflammatory marker transcription.
- These effects were significantly reduced in RIP3 knockout mice.
- RIP3 overexpression or Mitofilin knockdown in HK-2 cells increased cell death via the cGAS-STING-p65 pathway.
Conclusions:
- The RIP3-Mitofilin axis is a key driver of renal I/R injury.
- RIP3 translocation to mitochondria and subsequent interaction with Mitofilin initiates a cascade leading to inflammation and cell death.
- Targeting the RIP3-Mitofilin pathway may offer therapeutic strategies for renal I/R injury.
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