P-210 - Drug-induced effects on urea cycle enzymes associate with altered ammonia metabolism, NAD+ biosynthesis and mitochondrial protein acetylome

Abstract

Nitrogen metabolism in humans, as ureotelic organisms, involves reciprocal implications on mitochondrial function and redox homeostasis. The clinical use of valproic acid (VPA), a lysine deacetylase inhibitor, is potentially associated with undesired hyperammonemic encephalopathy (VHE). Our studies focused on: (i) mitochondrial processes conditioning acetyl-CoA production and (ii) Urea cycle (UC) modulating enzymes [1]. To understand if the acute VPA induced depleting effect on NAD homeostasis[2] correlates with sirtuin activity, we evaluated the mitochondrial protein acetylome by immunobloting. To investigate the hypothesis that CPS1 and OTC activities (SIRT5/3 targets) would be altered in vivo, Wistar rats were exposed to the epigenetic modulator VPA. Profiling liver UC and krebs cycles intermediates using targeted mass spectrometry-based methods enabled to characterize specific mitochondrial enzymes function. CPS1 and OTC activity were found to be significantly decreased at the onset of therapy and after repeated drug dosing, respectively. Results account to elucidate preventive strategies for VHE and to gain insights on signaling metabolites-driven adaptations in liver cells and mitonuclear processes.