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Extracellular Vesicle Mitochondrial DNA Reflects Podocyte Mitochondrial Stress and Is Associated with Relapse in

Robert L Myette1,2,3, Chet E Holterman2, Mayra Trentin-Sonoda2

  • 1Division of Pediatric Nephrology, Children's Hospital of Eastern Ontario Research Institute & Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON K1H 8L1, Canada.

International Journal of Molecular Sciences
|August 14, 2025
PubMed

Insights

Mitochondrial stress in podocytes releases extracellular vesicles containing mitochondrial DNA (mtDNA) in children with nephrotic syndrome. This finding may explain idiopathic pediatric nephrotic syndrome.

Area of Science:

  • Nephrology
  • Cell Biology
  • Mitochondrial Biology

Background:

  • Idiopathic childhood nephrotic syndrome is a common kidney disorder characterized by proteinuria, hypoalbuminemia, and edema.
  • Podocyte dysfunction is a key factor in the pathogenesis of nephrotic syndrome.
  • Extracellular vesicles (EVs) released by stressed cells can serve as biomarkers reflecting their cell of origin.

Purpose of the Study:

  • To investigate the role of mitochondrial DNA (mtDNA) within urinary large extracellular vesicles (LEVs) in idiopathic childhood nephrotic syndrome.
  • To determine if podocyte mitochondrial stress contributes to the release of mtDNA-containing LEVs.
  • To explore the therapeutic potential of prednisolone in modulating this pathway.

Main Methods:

  • In vitro studies using podocytes to assess LEV release and mtDNA content under stress.
  • In vivo studies using a puromycin aminonucleoside (PAN) nephrosis rat model.
  • Electron microscopy to evaluate podocyte foot process effacement.
  • Analysis of urinary LEVs for mtDNA content in rats and children with nephrotic syndrome.

Main Results:

  • Podocytes release LEVs containing mtDNA, driven by mitochondrial stress.
  • Rats with PAN-induced nephrosis exhibited increased urinary LEVs with elevated mtDNA and podocyte foot process effacement.
  • Prednisolone treatment reduced mitochondrial stress and mtDNA content in LEVs in vitro.
  • Urinary LEVs from children with nephrotic syndrome contained mtDNA, with enrichment in the podocyte-derived fraction.

Conclusions:

  • Podocyte mitochondrial stress is a potential mechanism underlying non-genetic, idiopathic pediatric nephrotic syndrome.
  • Urinary LEVs containing mtDNA may serve as a biomarker for podocyte injury in this condition.
  • Targeting mitochondrial stress could be a therapeutic strategy for pediatric nephrotic syndrome.

Keywords:
extracellular vesiclesmitochondrianephrotic syndromepediatrics

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