Comparative Analysis of the Impact of Mitochondrial Dysfunction on Endotheliopathy in Pediatric Sepsis and Diabetic Ketoacidosis

• Somin Park, Biomedical Engineering, University of Delaware

• Subir Kumar Roy Chowdhury, Critical Care Mitochondrial Unit, Nemours Children’s Hospital
• Scott Weiss, Pediatrics & Pathology and Genomic Medicine, & Critical Care Mitochondrial Unit, Thomas Jefferson University & Nemours Children’s Hospital

Organ dysfunction such as acute kidney injury (AKI) and endotheliopathy (EP) is associated with adverse outcomes in pediatric critical illnesses, but mechanisms remain poorly understood, with no targeted therapies. Mitochondrial dysfunction contributes to the pathophysiology of sepsis and diabetic ketoacidosis (DKA), yet systemic inflammatory mediators causing endothelial mitochondrial dysfunction have not been identified. We hypothesize that systemic mitochondrial dysfunction and plasma cytokines and matrix metalloproteinases (MMPs) impair mitochondrial function in endothelial and kidney cells. In Aim 1, we will measure plasma biomarkers of EP and AKI and mitochondrial DNA (mtDNA). In Aim 2, we will assess mitochondrial dysfunction ex vivo using a human umbilical vein endothelial cell (HUVEC) and human embryonic kidney 293 cell (HEK293) reporter assay. We expect high levels of EP and AKI biomarkers and mtDNA to correlate with decreased mitochondrial respiration, supporting a role for circulating mediators in endothelial and kidney mitochondrial dysfunction. In Aim 3, we will identify mediators that cause mitochondrial dysfunction in children with sepsis- and DKA-associated organ dysfunction. Elevated mediators associated with EP and AKI, mtDNA, and reduced mitochondrial respiration will be tested using targeted inhibitors in our reporter assay. By comparing cytokine and MMP profiles across children with sepsis and DKA, we will identify candidate proteins most likely to drive mitochondrial dysfunction. These studies will determine whether mitochondrial dysfunction is linked to organ injury and may reveal strategies to mitigate adverse outcomes in pediatric patients with critical illnesses.