Mitochondrial NAD(P)(+) Transhydrogenase is Unevenly Distributed in Different Brain Regions, and its Loss Causes Depressive-like Behavior and Motor Dysfunction in Mice

Author(s)

Francisco, Annelise ^[1] ; Engel, Daiane F. ^[2] ; Figueira, Tiago R. ^[3] ; Rogerio, Fabio ^[4] ; de Bem, Andreza F. ^[5] ; Castilho, Roger F. ^[1]

Affiliation

^[1] Univ Campinas UNICAMP, Sch Med Sci, Dept Clin Pathol, BR-13083887 Campinas, SP - Brazil

^[2] Univ Campinas UNICAMP, Obes & Comorbid Res Ctr, Campinas, SP - Brazil

^[3] Univ Sao Paulo, Sch Phys Educ & Sport Ribeirao Preto, Ribeirao Preto, SP - Brazil

^[4] Univ Campinas UNICAMP, Sch Med Sci, Dept Anat Pathol, Campinas, SP - Brazil

^[5] Univ Brasilia, Inst Biol Sci, Dept Physiol Sci, Brasilia, DF - Brazil

• Document type: Journal article
• Source: Neuroscience; v. 440, p. 210-229, AUG 1 2020.
• Web of Science Citations: 0

Abstract

NAD(P)(+) transhydrogenase (NNT) links redox states of the mitochondrial NAD(H) and NADP(H) via a reaction coupled to proton-motive force across the inner mitochondrial membrane. NNT is believed to be ubiquitously present in mammalian cells, but its expression may vary substantially in different tissues. The present study investigated the tissue distribution and possible roles of NNT in the mouse brain. The pons exhibited high NNT expression/activity, and immunohistochemistry revealed intense NNT labeling in neurons from brainstem nuclei. In some of these regions, neuronal NNT labeling was strongly colocalized with enzymes involved in the biosynthesis of 5-hydroxytryptamine (5-HT) and nitric oxide (center dot NO), which directly or indirectly require NADPH. Behavioral tests were performed in mice lacking NNT activity (Nnt(-/-), mice carrying the mutated Nnt(C57BL/6J) allele from the C57BL/6J strain) and the Nnt(+/+) controls. Our data demonstrated that aged Nnt(-/-) mice (18-20 months old), but not adult mice (3-4 months old), showed an increased immobility time in the tail suspension test that was reversed by fluoxetine treatment, providing evidence of depressive-like behavior in these mice. Aged Nnt(-/-) mice also exhibited behavioral changes and impaired locomotor activity in the open field and rotarod tests. Despite the colocalization between NNT and center dot NO synthase, the S-nitrosation and cGMP levels were independent of the Nnt genotype. Taken together, our results indicated that NNT is unevenly distributed throughout the brain and associated with 5-THergic and center dot NOergic neurons. The lack of NNT led to alterations in brain functions related to mood and motor behavior/performance in aged mice. (c) 2020 IBRO. Published by Elsevier Ltd. All rights reserved. (AU)

• FAPESP's process: 17/17728-8 - Mitochondrial function and dysfunction: implications for aging and associated diseases
• Grantee: Aníbal Eugênio Vercesi
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 15/22063-0 - Antioxidant Role of the Nicotinamide Nucleotide Transhydrogenase (NNT) in the Central Nervous System - Morphofunctional characterization in control mice and spontaneously Nnt gene mutant mice.
• Grantee: Annelise Francisco
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/01360-4 - Characterization of the role of the GPR40 receptor in the modulation of precursors of POMC neurons in the adult hypothalamus and its influence on the control of energy homeostasis
• Grantee: Daiane Fátima Engel
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 20/05202-4 - The role of mitochondrial NAD(P)+ transhydrogenase in monoaminergic neurotransmission and neurodegeneration in mice
• Grantee: Annelise Francisco
• Support type: Scholarships in Brazil - Post-Doctorate