Pathophysiological roles of mitochondrial NAD(P)+ transhydrogenase

• Grant number: 23/00229-0
• Support Opportunities: Research Projects - Thematic Grants
• Start date: May 01, 2024
• End date: 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): 25/12046-2 - Characterization of the Expression and Activity of Mitochondrial NAD(P)+ Transhydrogenase (NNT) in Brown Adipose Tissue of Mice, BP.IC; 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)

Scientific publications

(6)

(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)

SANTOS, GIOVANNA LEITE; COSTA, ERICKA FRANCISLAINE DIAS; DALLA COSTA, ANA PAULA; ZANESCO, ARIANE MARIA; SIMOES, MARCELA REYMOND; ROGERIO, FABIO; DEMOLIN, DANIELE MASSELLI RODRIGUES; NAVARRO, CLAUDIA DANIELE CARVALHO; VELLOSO, LICIO AUGUSTO; FRANCISCO, ANNELISE; et al. Influence of Mitochondrial NAD(P) ⁺ Transhydrogenase (NNT) on Hypothalamic Inflammation and Metabolic Dysfunction Induced by a High-Fat Diet in Mice. Hormone and Metabolic Research, v. N/A, p. 9-pg., 2024-10-31. (23/00229-0, 23/06469-2, 17/17728-8)

ZEMNIACAK, ANGELA BEATRIS; RIBEIRO, RAFAEL TEIXEIRA; DAS NEVES, GUSTAVO MACHADO; CUNHA, SAMELA DE AZEVEDO; TAVARES, TAILINE QUEVEDO; CARVALHO, ANDREY VINICIOS SOARES; NETTO, CARLOS ALEXANDRE; CASTILHO, ROGER FRIGERIO; WAJNER, MOACIR; AMARAL, ALEXANDRE UMPIERREZ. α-Ketoisocaproic Acid Disrupts Mitochondrial Bioenergetics in the Brain of Neonate Rats: Molecular Modeling Studies of α-ketoglutarate Dehydrogenase Subunits Inhibition. Neurochemical Research, v. 50, n. 1, p. 15-pg., 2025-02-01. (23/00229-0, 17/17728-8)

SILVA, GUSTAVO H. RODRIGUES DA; MENDES, LUIS F.; GERONIMO, GABRIELA; DE MOURA, LUDMILLA D.; RUAS, JULIANA S.; CASTILHO, ROGER F.; CORDEIRO, HELON G.; FERREIRA, CARMEN, V; DE PAULA, ENEIDA; DUARTE, IOLA F.. Schwann cells exposed to articaine display distinct toxic pathways compared to lidocaine. Chemico-Biological Interactions, v. 406, p. 12-pg., 2024-11-29. (18/24814-0, 23/00229-0, 14/25372-0)

NAVARRO, CLAUDIA D. C.; FRANCISCO, ANNELISE; COSTA, ERICKA F. D.; COSTA, ANA P. DALLA; SARTORI, MARINA R.; BIZERRA, PAULO F. V.; SALGADO, ANDREIA R.; FIGUEIRA, TIAGO R.; VERCESI, ANIBAL E.; CASTILHO, ROGER F.. Aging-dependent mitochondrial bioenergetic impairment in the skeletal muscle of NNT-deficient mice. Experimental Gerontology, v. 193, p. 12-pg., 2024-05-25. (19/20855-7, 23/00229-0, 20/05202-4, 17/17728-8, 23/06469-2)

BRUNETTA, HENVER S.; JUNG, ANNA S.; VALDIVIESO-RIVERA, FERNANDO; ZANI, STEPHENY C. DE CAMPOS; GUERRA, JOEL; FURINO, VANESSA O.; FRANCISCO, ANNELISE; BERCOT, MARCELO; MORAES-VIEIRA, PEDRO M.; KEIPERT, SUSANNE; et al. IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat. EMBO Journal, v. 43, n. 21, p. 22-pg., 2024-09-16. (21/08354-2, 17/17728-8, 13/07607-8, 19/21852-1, 22/00358-1, 23/07882-0, 20/14725-0, 22/13145-6, 23/00229-0)

QUEIROZ, ANNE L. F.; GARCIA, CHRISTOPHER B.; SILVA, JOAO P. M. O.; CAVALINI, DIEGO F. A.; ALEXANDRINO, ANDRE V.; CUNHA, ANDERSON F.; VERCESI, ANIBAL E.; CASTILHO, ROGER F.; SHIGUEMOTO, GILBERTO E.. Preventive Effects of Resistance Training on Hemodynamics and Kidney Mitochondrial Bioenergetic Function in Ovariectomized Rats. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 26, n. 1, p. 27-pg., 2025-01-01. (23/00229-0, 17/17728-8)