Pathophysiological roles of mitochondrial NAD(P)+ transhydrogenase

• Grant number: 23/00229-0
• Support Opportunities: Research Projects - Thematic Grants
• Duration: May 01, 2024 - April 30, 2029
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Roger Frigério Castilho
• Grantee: Roger Frigério Castilho
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Alexandre Leite Rodrigues de Oliveira ; Aníbal Eugênio Vercesi ; Fábio Rogério ; José Andrés Yunes ; Sergio Akira Uyemura ; Tiago Rezende Figueira
• Associated scholarship(s): 24/10257-3 - The Role of Mitochondrial NAD(P)+ Transhydrogenase (NNT) in Neuroinflammatory Response and Glioblastoma Cell Proliferation in Culture, BP.PD

Abstract

Proton-translocating NAD(P)+ transhydrogenase (NNT) is a transmembrane protein located in the inner mitochondrial membrane that catalyzes the reversible reduction reaction of NADP+ by NADH, with generation of NADPH and NAD+, coupled to the entry of a proton from the intermembrane space to the mitochondrial matrix. NNT is ubiquitously expressed in mammals and its function is related to the maintenance of mitochondrial and cellular homeostatic mechanisms. The direct NNT reaction is an important source of NADPH in the mitochondrial matrix, providing reductive potential for biosynthetic and antioxidant pathways, such as detoxification of reactive oxygen species by glutathione reductase/glutathione peroxidase and thioredoxin reductase/peroxiredoxin systems. This Project aims to better understand the pathophysiological roles of NNT and its relationship with the mitochondrial NADP redox state, through four lines of investigation, namely: i) NNT and NADP redox state in bioenergetics and mitochondrial permeability transition; ii) Pathophysiological roles of NNT: studies in Nnt-/- mice; iii) NNT in redox signaling, cell proliferation and viability; and iv) NNT in human health and in glioblastomas. The development of the present Project will contribute for a better understanding of the importance of NNT for the mitochondrial physiology, cell biology and human health. (AU)