Study of the role of HIF-1a in the induction of mitochondria dysfunction in inflammatory macrophages.

• Grant number: 25/03812-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2025
• End date: April 30, 2027
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: Lincon Felipe Lima Silva
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 20/16030-0 - Immunometabolic adaptation of tissue resident macrophages in health and disease, AP.TEM

Abstract

Mitochondrial dynamics are essential for cellular adaptation, yet their regulation in immune cells and impact on immune responses remain poorly understood. This study investigates the role of hypoxia-inducible factor-1a (HIF-1a) in the development of mitochondrial dysfunction during macrophage-mediated inflammation. Preliminary findings indicate that HIF-1a stabilization occurs prior to mitochondrial impairment in LPS-activated macrophages, suggesting that such stabilization is more likely a consequence than the primary cause of dysfunction. Our working hypothesis posits that mitochondrial dysfunction-mediated in part by inducible nitric oxide synthase (iNOS)-derived nitric oxide inhibiting key electron transport chain complexes-drives the stabilization of HIF-1a. To evaluate this, we employ genetic models using conditional knockout mice for HIF-1a and VHL alongside pharmacological interventions to assess the impact of altered HIF-1a levels on mitochondrial function. In parallel, the study explores how HIF-1a modulates mitochondrial gene expression through chromatin immunoprecipitation sequencing (ChIP-Seq) and gene expression analyses. The experimental design incorporates in vitro, in vivo, and ex vivo approaches to assess metabolic profiles (via measurements of extracellular acidification and oxygen consumption), mitochondrial morphology (using confocal and electron microscopy), and the activation of relevant signaling pathways. This comprehensive analysis aims to elucidate the interplay between HIF-1a stabilization, mitochondrial dynamics, and the metabolic reprogramming of inflammatory macrophages.