Role of mitochondrial function in the oxidative stress profile of children with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by severe obesity and associated with increased oxidative stress. This phenomenon is partly attributed to elevated levels of reactive oxygen species (ROS), which promote inflammation and metabolic dysfunction, contributing to significant metabolic complications. Growth hormone (GH) treatment is widely used in children with PWS due to its well-documented benefits, including improvements in body composition, motor development, and cognitive function. In this study, we assessed the oxidative stress profile in children with PWS treated with GH. Since obesity and inflammation are well-established contributors to oxidative stress, values obtained from non-syndromic obese patients were included as a reference, allowing the findings to be contextualized within the framework of oxidative stress. The study included 12 GH-treated PWS children with a mean age of 15 years and 11 non-syndromic obese patients with a mean age of 14 years. Flow cytometry was employed as the primary method to analyse markers of oxidative stress, inflammation, and mitochondrial function in both groups. Additionally, this technique enabled the identification of immune cell populations associated with chronic inflammation, acute inflammation, and immune response, providing a comprehensive understanding of the underlying mechanisms. Despite PWS children having 4- to 6-fold lower glutathione (GSH) levels, PWS children demonstrated 2- to 3.5-fold higher mitochondrial activity, increasing their antioxidant capacity and reducing lipid peroxidation and protein carbonylation by up to 2-fold compared to non-syndromic obese children. GH-treated PWS children also showed lower mitochondrial dysfunction under oxidative conditions, higher cell viability, and elevated inflammatory biomarkers, suggesting a link to senescence and premature ageing. GH-treated PWS children, despite being non-obese, exhibited higher systemic inflammation compared to the non-syndromic obese group, alongside significant differences in oxidative stress and inflammatory markers. These findings suggest that mitochondrial pathways may play a role in antioxidant responses in PWS, highlighting the complexity of oxidative stress and its potential contribution to premature ageing in this condition. Understanding these mechanisms and the role of GH treatment could inform the development of targeted therapies to better manage oxidative stress and inflammation, ultimately improving the quality of life for PWS children.