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

## TL;DR

Podocyte mitochondrial stress leads to the release of extracellular vesicles containing mitochondrial DNA, which is linked to relapse in childhood nephrotic syndrome.

## Contribution

Podocytes release extracellular vesicles with mitochondrial DNA under stress, a novel mechanism in nephrotic syndrome.

## Key findings

- Podocytes release large extracellular vesicles containing mitochondrial DNA when under mitochondrial stress.
- Prednisolone reduces mitochondrial stress and mtDNA content in extracellular vesicles in vitro.
- Children with nephrotic syndrome have mtDNA in urinary extracellular vesicles, particularly in the podocyte-derived fraction.

## Abstract

Idiopathic childhood nephrotic syndrome is a common glomerulopathy comprising proteinuria, hypoalbuminemia, and edema. Podocyte dysfunction is central to this disease process. Extracellular vesicles are released from stressed cells and can represent a molecular snapshot of the parent cell of origin. We previously showed that urinary large extracellular vesicles (LEVs) derived from podocytes are increased in patients with nephrotic syndrome relapse. Here, we investigated the role of mitochondrial DNA (mtDNA) within LEVs both in vitro and in vivo, revealing the novel finding that podocytes release LEVs containing mtDNA, driven by mitochondrial stress. A puromycin aminonucleoside nephrosis rat model showed foot process effacement on electron microscopy and urinary LEVs with significantly increased mtDNA. Prednisolone, which drives remission in nephrotic syndrome in children, attenuated mitochondrial stress and reduced the amount of mtDNA content within LEVs in vitro. Lastly, urinary LEVs from children with nephrotic syndrome also contain mtDNA, and it is the podocyte LEV-fraction which is preferentially enriched. Overall, these data support a potential mechanism of podocyte mitochondrial stress in non-genetic, idiopathic pediatric nephrotic syndrome.