The Role of Cellular Stress, Antioxidant System Response, Mitochondrial Function, and Metabolic Alterations in the...

Propionic acidemia (PA) is a rare, life-threatening inherited metabolic disorder. Despite early therapy and effective metabolic control with current treatments, patients with PA face recurrent severe metabolic decompensations and multisystemic complications. The exact pathophysiological mechanisms of these complications remain unclear. This systematic review aims to enhance understanding of molecular mechanisms underlying PA by simultaneously evaluating ROS-mediated cellular stress, antioxidant response, mitochondrial dysfunction, metabolic alterations, and mitohormesis. For this purpose, a literature search was conducted across PubMed, Scopus, ScienceDirect, Web of Science, Cochrane Library, and ClinicalTrials.gov databases. This review included 42 experimental studies, comprising 13 human studies, 27 animal studies, and 2 studies involving both animals (rat and mice/mouse) and humans. As a result: (i) both oxidative and reductive stress can occur in PA, with individual variability; (ii) ROS-mediated cellular damage generally accompanies PA; (iii) the antioxidant response can vary depending on the type, severity, and duration of cellular stress; (iv) secondary mitochondrial dysfunction accompanies PA; (v) ROS-mediated stress effects correlate with alterations in interconnected metabolic pathways in PA; and (vi) mitohormesis can play a role in PA. In conclusion, using antioxidants or preventive treatments for PA without assessing cellular stress during diagnosis and treatment may further disturb the delicate oxidant-antioxidant balance. Simultaneous evaluation of ROS-mediated cellular stress and associated pathways in PA has potential to both revise existing treatments and discover new therapies, thereby improving the quality of life and longevity of patients with PA, as well as elucidating the unclear pathophysiology of PA.