Renal Protection Driven by Peroxisome Activity, Proximal Tubule Park7, and Protein Succinylation
- AKI: Mechanisms - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Pfister, Katherine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Young, Victoria, Lake Erie College of Osteopathic Medicine Bradenton Campus, Bradenton, Florida, United States
- Silva Barbosa, Anne Caroline, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Goetzman, Eric S., UPMC, Pittsburgh, Pennsylvania, United States
- Schilling, Birgit, Buck Institute for Research on Aging, Novato, California, United States
- Sims-Lucas, Sunder, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Acute Kidney injury (AKI) is an unfortunately frequent disease acquired during hospitalization with nearly 1 in 5 patients exhibiting some form of AKI. With the recent COVID-19 epidemic increasing instances of hospitalization, the burden that AKI and ensuing Chronic Kidney Disease (CKD) has on healthcare underlines the critical need for early detection, protection, and treatment for AKI. To attenuate AKI occurrence therapeutically we need a better understanding of the physiological and cellular mechanisms underlying damage. The most pronounced effect of AKI is on the Proximal Tubule Epithelial Cells (PTECs) which have the highest metabolic activity and are therefore most susceptible to damage after ischemia, sepsis, or transplant stress. This damage causes an increase in radical oxygen species, oxidative protein stress, and decreased functionality of mitochondrial Fatty Acid Oxidation (FAO) enzymes.
Our approach to protect from long-lasting tissue damage is by modulating the metabolic regimen and activating FAO in peroxisomes, a normally underused metabolic organelle. Large classes of proteins can be modulated rapidly and reversibly through the activity of enzymes that ligate Posttranslational Modifications (PTMs). We have previously shown that succinylation of lysine residues on metabolic proteins can be protective during AKI, specifically when the activity of the desuccinylase Sirtuin 5 is inhibited.
Maintenance of the succinylome in Sirtuin 5 knockout tissue requires the activity of a second PTM ligating enzyme, the deglycase Park7. Park 7 is activated by oxidative stress and has been linked to apoptotic protection and minimizing CKD through reduction of Advanced Glycation Endproducts. Mass spectrometry analysis of kidney lysates point towards a protective combination of activated Park7 and deactivated Sirtuin 5 increasing peroxisomal FAO. This relationship is confirmed by the use of a diet-induced peroxisome upregulation using dicarboxylic acid (DCA) supplementation. The protection seen with DCA after AKI is significantly dependent on functioning Park7.
We conclude that a rapid and effective target for AKI treatment can be found by analyzing and maintaining the succinylome of PTECs and we hope to harness this mechanism to develop novel therapies for AKI.
- NIDDK Support