Impact of ROS production at different sites and times on mitochondrial Ca2+ dynamics in pancreatic beta cells

• Grant number: 25/11333-8
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2025
• End date: May 31, 2027
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Eloisa Aparecida Vilas Boas
• Grantee: Lucas Rafael Pereira Camara
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 24/17148-5 - Interaction between redox state and calcium in the pathophysiology of type 1 and 2 diabetes mellitus, AP.R

Abstract

Pancreatic islet beta cells are responsible for the synthesis and secretion of insulin, which regulates blood glucose levels by promoting glucose uptake into certain cells, in addition to stimulating the formation of energy reserves and inhibiting their degradation. Alterations in insulin secretion, whether or not associated with impaired hormone action, lead to a condition of chronic hyperglycemia known as diabetes mellitus (DM). Two of the main intracellular signaling molecules involved in the pathophysiology of pancreatic beta cells are calcium (Ca²¿) and reactive oxygen species (ROS). Both are essential for insulin secretion. Therefore, situations that cause an imbalance in Ca²¿ homeostasis and/or in the balance between ROS production and removal may contribute to beta cell dysfunction in both main types of DM, type 1 (T1DM) and type 2 (T2DM).ROS and Ca²¿ are likely to have much greater relevance near their sites of production, i.e., within specific intracellular microdomains. This is because ROS are produced and rapidly scavenged by the intracellular antioxidant system, and cytosolic Ca²¿ is maintained at low concentrations. As a result, Ca²¿-dependent signaling requires its mobilization from the extracellular space and/or intracellular stores such as the mitochondria and endoplasmic reticulum. Mitochondria are a major source of oxidants and also possess a large Ca²¿ storage capacity in their matrix.Our group has already demonstrated the temporal dynamics of oxidant production in pancreatic islets exposed to conditions that mimic T1DM and T2DM, as well as the relevance of mitochondria and NADPH oxidase (NOX) in this context. Some studies suggest that redox signaling can affect Ca²¿ homeostasis, and that Ca²¿ signaling can, in turn, influence oxidant production. However, causal and hierarchical relationships in response to stress remain unclear, and we are therefore still unable to define targeted modulation strategies.Our hypothesis is that oxidant production by mitochondria and/or via NOX negatively impacts mitochondrial Ca²¿ signaling, impairing the function of this organelle in the context of diabetes. Based on this, our objective is to evaluate the impact of mitochondrial and/or NOX-derived ROS production, at specific time points previously defined in our studies, on mitochondrial Ca²¿ dynamics in pancreatic beta cells. (AU)