RIP3 Translocation into Mitochondria Promotes Mitofilin Degradation to Increase Inflammation and Kidney Injury after Renal Ischemia–Reperfusion

Yansheng Feng, Abdulhafiz Imam Aliagan, Nathalie Tombo, Derrick Draeger, Jean C. Bopassa

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number1894
JournalCells
Volume11
Issue number12
DOIs
StatePublished - Jun 1 2022

Keywords

  • acute kidney injury (AKI)
  • cGAS–STING–p65 pathway and inflammation
  • inner mitochondrial membrane protein (immt
  • mitochondrial dysfunction
  • mitochondrial structural integrity and function
  • mitofilin)
  • mtDNA release
  • receptor-interacting protein kinase 3 (RIP3)

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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