Antioxidant Role of the Nicotinamide Nucleotide Transhydrogenase (NNT) in the Central Nervous System - Morphofunctional characterization in control mice and spontaneously Nnt gene mutant mice.

• Grant number: 15/22063-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): March 01, 2016
• Effective date (End): February 29, 2020
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Roger Frigério Castilho
• Grantee: Annelise Francisco
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The nicotinamide nucleotide transhydrogenase (NNT) is a transmembrane protein located in the inner mitochondrial membrane that catalyzes the reduction of NADP+ by NADH producing NADPH and NAD+, coupled to the transport of protons from the intermembrane space to the mitochondrial matrix. This protein is expressed in all mammalian and its function is related to the maintenance of mitochondrial and cellular homeostatic mechanisms, such as reactive oxygen species metabolism by glutathione reductase/peroxidase and thioredoxin/peroxiredoxin systems. Pathological changes like familial deficiency of glucocorticoids and mineralocorticoids in humans are linked to NNT deficiency. NNT activity also has relevance in the metabolism and proliferation of tumor cells. While there have been advances in research on the role of NNT in cellular metabolism, details of its physiology and its influence in pathophysiological states have yet to be elucidated. Thus, this project aims to characterize the NNT expression and activity in mouse brains, assess the role of NNT in reactive oxygen species release by brain mitochondria and finally, investigate the importance of NNT in an experimental model for Parkinson's disease. For this purpose, comparative studies will be conducted using C57BL/6 mice with a spontaneous mutation in the NNT gene (C57Unib.B6-NNT-/-) which results in absence of protein expression, and congenic mice with normal NNT expression (C57Unib.B6-NNT+/+). Colonies of these mice are already established in our laboratory and are a suitable model for studying pathophysiological aspects of NNT.

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

FRANCISCO, ANNELISE; ENGEL, DAIANE F.; FIGUEIRA, TIAGO R.; ROGERIO, FABIO; DE BEM, ANDREZA F.; CASTILHO, ROGER F.. Mitochondrial NAD(P)(+) Transhydrogenase is Unevenly Distributed in Different Brain Regions, and its Loss Causes Depressive-like Behavior and Motor Dysfunction in Mice. Neuroscience, v. 440, p. 210-229, AUG 1 2020. (17/17728-8, 15/22063-0, 18/01360-4, 20/05202-4)

RONCHI, JULIANA APARECIDA; FRANCISCO, ANNELISE; CORREA PASSOS, LUIZ AUGUSTO; FIGUEIRA, TIAGO REZENDE; CASTILHO, ROGER FRIGERIO. The Contribution of Nicotinamide Nucleotide Transhydrogenase to Peroxide Detoxification Is Dependent on the Respiratory State and Counterbalanced by Other Sources of NADPH in Liver Mitochondria. Journal of Biological Chemistry, v. 291, n. 38, p. 20173-20187, SEP 16 2016. (11/50400-0, 15/22063-0)

NAVARRO, CLAUDIA D. C.; FIGUEIRA, TIAGO R.; FRANCISCO, ANNELISE; DAL'BO, GENOEFA A.; RONCHI, JULIANA A.; ROVANI, JULIANA C.; ESCANHOELA, CECILIA A. F.; OLIVEIRA, HELENA C. F.; CASTILHO, ROGER F.; VERCESI, ANIBAL E.. Redox imbalance due to the loss of mitochondrial NAD(P)-transhydrogenase markedly aggravates high fat diet-induced fatty liver disease in mice. Free Radical Biology and Medicine, v. 113, p. 190-202, DEC 2017. (14/02819-0, 11/50400-0, 15/22063-0, 13/07607-8)

BICEGO, RAFAELA; FRANCISCO, ANNELISE; RUAS, JULIANA S.; SIQUEIRA-SANTOS, EDILENE S.; CASTILHO, ROGER F.. Undesirable effects of chemical inhibitors of NAD(P)(+) transhydrogenase on mitochondrial respiratory function. Archives of Biochemistry and Biophysics, v. 692, p. 12-pg., 2020-10-15. (17/17728-8, 20/05202-4, 15/22063-0)

FRANCISCO, ANNELISE; RONCHI, JULIANA A.; NAVARRO, CLAUDIA D. C.; FIGUEIRA, TIAGO R.; CASTILHO, ROGER F.. Nicotinamide nucleotide transhydrogenase is required for brain mitochondrial redox balance under hampered energy substrate metabolism and high-fat diet. Journal of Neurochemistry, v. 147, n. 5, p. 663-677, DEC 2018. (17/17728-8, 15/22063-0)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

FRANCISCO, Annelise. Nicotinamide nucleotide transhydrogenase (NNT) in the central nervous system: morphofuncional characterization in control mice and mice carrying a spontaneous mutation in Nnt gene. 2020. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas Campinas, SP.