Nicotinamide nucleotide transhydrogenase is required for brain mitochondrial redox balance under hampered energy substrate metabolism and high-fat diet

Author(s)

Francisco, Annelise ^[1] ; Ronchi, Juliana A. ^[1] ; Navarro, Claudia D. C. ^[1] ; Figueira, Tiago R. ^{[2, 1]} ; Castilho, Roger F. ^[1]

Affiliation

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

^[2] Univ Sao Paulo, Sch Phys Educ & Sport Ribeirao Preto, Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: Journal of Neurochemistry; v. 147, n. 5, p. 663-677, DEC 2018.
• Web of Science Citations: 0

Abstract

Among mitochondrial NADP-reducing enzymes, nicotinamide nucleotide transhydrogenase (NNT) establishes an elevated matrix NADPH/NADP(+) by catalyzing the reduction of NADP(+) at the expense of NADH oxidation coupled to inward proton translocation across the inner mitochondrial membrane. Here, we characterize NNT activity and mitochondrial redox balance in the brain using a congenic mouse model carrying the mutated Nnt gene from the C57BL/6J strain. The absence of NNT activity resulted in lower total NADPH sources activity in the brain mitochondria of young mice, an effect that was partially compensated in aged mice. Nonsynaptic mitochondria showed higher NNT activity than synaptic mitochondria. In the absence of NNT, an increased release of H2O2 from mitochondria was observed when the metabolism of respiratory substrates occurred with restricted flux through relevant mitochondrial NADPH sources or when respiratory complex I was inhibited. In accordance, mitochondria from Nnt(-/-) brains were unable to sustain NADP in its reduced state when energized in the absence of carbon substrates, an effect aggravated after H2O2 bolus metabolism. These data indicate that the lack of NNT in brain mitochondria impairs peroxide detoxification, but peroxide detoxification can be partially counterbalanced by concurrent NADPH sources depending on substrate availability. Notably, only brain mitochondria from Nnt(-/-) mice chronically fed a high-fat diet exhibited lower activity of the redox-sensitive aconitase, suggesting that brain mitochondrial redox balance requires NNT under the metabolic stress of a high-fat diet. Overall, the role of NNT in the brain mitochondria redox balance especially comes into play under mitochondrial respiratory defects or high-fat diet. (AU)

• FAPESP's process: 17/17728-8 - Mitochondrial function and dysfunction: implications for aging and associated diseases
• Grantee: Aníbal Eugênio Vercesi
• Support Opportunities: 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 Opportunities: Scholarships in Brazil - Doctorate