Involvement of energy metabolism and oxidative stress in cell death

• Grant number: 03/08514-1
• Support type: Research Projects - Thematic Grants
• Duration: February 01, 2004 - March 31, 2007
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Aníbal Eugênio Vercesi
• Grantee: Aníbal Eugênio Vercesi
• Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Co-Principal Investigators: Alicia Juliana Kowaltowski ; Roger Frigério Castilho

Abstract

Many diseases are related to changes in energy metabolism and impairment of Ca2+, Na+, H+ or K+ homeostasis, reactive oxygen species (ROS) generation or the activation of mitochondrially-controlled cell death. Our project seeks to enhance our comprehension of these diseases, studying energy metabolism in vitro and applying this knowledge toward the understanding of cellular and in vivo models of diseases known to be associated with energy metabolism defects including stroke, methyl-malonic acidemia, Huntington's and Parkinson's diseases. The main goals of our project are: 1) to understand the mechanisms through which mitochondrial energy metabolism is regulated in mammals, and the implications of this regulation on reactive oxygen species (ROS) release. We will determine the role of mammalian uncoupling proteins and mitochondrial ATP-sensitive K+ channels in the regulation of mitochondrial electron transport and ROS formation. The effect of different components and inhibitors of the electron transport chain on ROS generation will also be evaluated, in addition to the effects of mitochondrial proteins involved in apoptosis; 2) to study energy metabolism, oxidative stress and cell death in pathogenic fungi. Fungi from the Candida and Cryptococcus genuses have complex electron transport networks which include many branched electron pathways. We will study the different electron transport pathways, determine the effects of antimicotic agents and establish the role of each pathway in the control of fungal ROS generation and cellular vitality; 3) to understand the effect of dislipidemias on mitochondrial integrity, ROS release and cell death. We will study the mitochondrial effects of hypercholesterolemia and hypertriglyceridemia on mitochondrial electron transport, ROS release, Ca2+ transport and mitochondrial membrane fluidity, using transgenic mice which present these dislipidemias. We will also determine the effect of dislipidemias on mitochondrial membrane permeabilization induced by oxidative stress. Finally, we will examine the effects of commercial drugs used to control these disorders on the mitochondrial parameters affected by hypercholesterolemia and hypertriglyceridemia; 4) to study alterations in energy metabolism related to neuronal cell death promoted by ischemia/reperfusion. We will measure high-energy phosphate levels, ion homeostasis and ROS release in neuronal cultures submitted to ischemia/reperfusion. The possible role of mitochondrial permeability transition and ATP-sensitive K+ channels in cell death associated to ischemia will be evaluated. We will algo study the mitochondrial effects of excitotoxic cell death induced by glutamate and glycine in cell cultures, since excitotoxicity is a prominent cause of ischemic cell death in neurons; 5) to study the involvement of energy metabolism failure in neurodegenerative diseases... (AU)