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Cellular Redox State Acts As Switch to Determine the Direction of NNT-Catalyzed Reaction in Cystic Fibrosis Cells

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Cellular Redox State Acts As Switch to Determine the Direction of NNT-Catalyzed Reaction in Cystic Fibrosis Cells International Journal of Molecular Sciences Article Cellular Redox State Acts as Switch to Determine the Direction of NNT-Catalyzed Reaction in Cystic Fibrosis Cells Maria Favia 1,2,* and Anna Atlante 1,* 1 Istituto di Biomembrane, Bioenergetica e Biotecnologie Molecolari (IBIOM)–CNR, Via G. Amendola 122/O, 70126 Bari, Italy 2 Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università di Bari, Via E. Orabona 4, 70126 Bari, Italy * Correspondence: [email protected] (M.F.); [email protected] (A.A.); Tel.: +39-080-592-9804 (M.F. & A.A.) Abstract: The redox states of NAD and NADP are linked to each other in the mitochondria thanks to the enzyme nicotinamide nucleotide transhydrogenase (NNT) which, by utilizing the mitochondrial membrane potential (mDY), catalyzes the transfer of redox potential between these two coenzymes, reducing one at the expense of the oxidation of the other. In order to define NNT reaction direction in CF cells, NNT activity under different redox states of cell has been investigated. Using spectropho- tometric and western blotting techniques, the presence, abundance and activity level of NNT were determined. In parallel, the levels of NADPH and NADH as well as of mitochondrial and cellular ROS were also quantified. CF cells showed a 70% increase in protein expression compared to the Wt sample; however, regarding NNT activity, it was surprisingly lower in CF cells than healthy cells (about 30%). The cellular redox state, together with the low mDY, pushes to drive NNT reverse reaction, at the expense of its antioxidant potential, thus consuming NADPH to support NADH production. At the same time, the reduced NNT activity prevents the NADH, produced by the reaction, from causing an explosion of ROS by the damaged respiratory chain, in accordance with Citation: Favia, M.; Atlante, A. the reduced level of mitochondrial ROS in NNT-loss cells. This new information on cellular bioener- Cellular Redox State Acts as Switch to getics represents an important building block for further understanding the molecular mechanisms Determine the Direction of responsible for cellular dysfunction in cystic fibrosis. NNT-Catalyzed Reaction in Cystic Fibrosis Cells. Int. J. Mol. Sci. 2021, 22, Keywords: nicotinamide nucleotide transhydrogenase; cystic fibrosis; mitochondria; glucose-6- 967. https://doi.org/10.3390/ phosphate dehydrogenase; NADPH; antioxidant ijms22020967 Received: 20 December 2020 Accepted: 16 January 2021 1. Introduction Published: 19 January 2021 Nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide Publisher’s Note: MDPI stays neutral phosphate (NADP) act as “electron carriers”. Despite their structural similarity, these with regard to jurisdictional claims in molecules—in their reduced forms, NADH and NADPH—are required to drive different published maps and institutional affil- and specific cellular processes [1–3]. In fact, if NAD, accepting electrons in catabolic path- iations. ways, requires its pool to be maintained in an oxidized state, in contrast, maintenance of the nuclear and mitochondrial genomes, cell signaling, antioxidative defense, redox balance and all anabolic reactions require the reductive power stored within NADPH [4,5]. An arsenal of NADPH-regenerating enzymes (NRE) identified in various metabolic pathways— among them Glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme and isocitrate Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. dehydrogenase—ensures that this pyridine nucleotide remains in its reduced form. These This article is an open access article enzymes are the main contributors of cellular NADPH pool [6] so much so that an increase distributed under the terms and in the expression of lipid synthesis or antioxidant defense genes is associated with the conditions of the Creative Commons induction of them [7–9], as well as the loss of one NADPH-producing enzyme can be Attribution (CC BY) license (https:// compensated by the induction of another [7]. creativecommons.org/licenses/by/ The complexity of NADPH homeostasis regulation in eukaryotic systems is essentially 4.0/). due to membranes being impermeable to NADPH. In this regard, it should be borne in mind Int. J. Mol. Sci. 2021, 22, 967. https://doi.org/10.3390/ijms22020967 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 967 2 of 13 that neither NAD(H) nor NADP(H) are transported across intracellular membranes [10,11], and multistep shuttles involving compartmentalized redox reactions are used to transfer electrons between the mitochondria and cytosol [12]. This organization facilitates the maintenance of different NADH/NAD and NADPH/NADP+ ratios in each subcellular location and allows for the execution of compartment-specific metabolic processes. Interestingly, the redox states of NAD and NADP are linked to each other in the mitochondria of many organisms since the enzyme nicotinamide nucleotide transhydro- genase (NNT), an integral protein of the inner mitochondrial membrane [13], acting by utilizing the mitochondrial membrane potential (mDY), catalyzes the transfer of redox potential between these two coenzymes, reducing one at the expense of the oxidation of the other [10,14]. In vivo the formation of NADPH by NNT, at the expense of NADH oxidation, is highly favored. Hence NADH, besides to be a source of fuel for the electron transport system to generate the mDY needed to support NNT activity [15], is also a substrate for NNT. It also appears that NNT is the major mitochondrial source of NADPH, contributing 45% of the total NADPH supply [16–18], so as to be considered a key antioxidant enzyme. However, under certain pathophysiological conditions, NNT reaction may change direction, i.e., to operate in reverse: this occurs at the expense of NADPH, thereby disrupting antioxidant defense [17,19,20]. Here, we show that the metabolic demand associated with the DF508 mutation reverses the direction of the NNT reaction, generating NADH from NADPH and NAD+, resulting in the antioxidant defense loss and metabolic adaption. 2. Results During infections associated to CF, a high NADPH level is needed due to augmented oxidative stress [21–24]. Recently, we found that CF cells have increased NADPH oxidase (NOX) activity and decreased glutathione reductase (GR) activity, both NADPH consuming enzymes (NCE), but with opposite role: if NOX utilizes NADPH to produce ROS, NADPH serves to recover the GSH level from GSSG in the GR reaction. Furthermore, we proved that both defective CFTR and NOX/GR activity imbalance contribute to NADPH and GSH level decrease and ROS overproduction in CF cells. In parallel, we detected low NADPH level [24,25]—likely due to lower G6PDH activity—and high NADH level, as expected, being its oxidation impaired since ETC activity decreased in CF [22–25]. Considering that the balance between the consumption of NADPH via NOX [25], and the regeneration of NADPH by NADPH regenerating enzymes, e.g., G6PDH, within the cytosol, may overall depend on metabolic/redox state of the cell, we suggest that NNT, enzyme providing a link between the NADP/NADPH and NAD/NADH pools and the proton motive force, may have a very important role for redox metabolic regulation in CF. 2.1. NNT Expression and Activity in CF Airway Cells In order to find out whether NNT expression and activity were altered in CF and, at the same time, to detect the direction of the reaction, we analyzed these characteristics in human bronchial epithelial cells using western blotting and spectrophotometry. Once the presence of NNT was ascertained, we measured the protein level: CF cells showed a 70% increase in protein expression compared to the Wt sample (Figure1A). Regarding NNT activity, it is to consider that NNT is the only enzyme to act coupling production of NADPH to the rate of aerobic respiration. Comparing CF and Wt samples, NNT activity was surprisingly lower in CF cells than healthy cells (about 30%), with activity rates of 52.6 ± 1.2 in the Control and 36.5 ± 0.5 nmol/min/mg cell protein in the CF group (Figure1B), values in line with Sheeran et al. [6] data in human heart mitochondria. In order to confirm that the effect was specific for NNT activity, S-nitrosoglutathione (GSNO, 1 mM), a strong inhibitor of NNT, was found to cause a collapse of the activity (Figure1C) [6]. Int. J. Mol. Sci. 2021, 22, 967 3 of 13 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 14 Figure 1. NNTNNT protein protein level level and and activity activity in in airway airway cells. cells. (A ()A NNT) NNT protein protein expression expression in Wt in Wtand and CF CFcells cells was was detected detected by Western by Western blot blot analyses. analyses. The The blot blot incubated incubated for each for each antibody antibody was wasstripped stripped and andreprobed reprobed with with anti ß anti‐actin ß-actin antibody. antibody. Protein Protein amount amount was expressed, was expressed, after afternormalization normalization with re with‐ respectspect to tocorresponding corresponding β‐actin,β-actin, as a as percentage a percentage of the of the content content inWt inWt cells cells to which to which a value a value of 100 of was 100 CCCP (3 μmol/L), OLIGO (1.5 ng/ml) and GSNO (1 mmol/L) were added 15 min before activity was CCCP (3 µmol/L), OLIGO (1.5 ng/ml) and GSNO (1 mmol/L) were added 15 min before activity determination. Values were subjected to statistical analysis (Wt, n = 4; CF, n = 5): (B), ° p < 0.05 when determination. Values were subjected to statistical analysis (Wt, n = 4; CF, n = 5): (B), ◦ p < 0.05 comparing CF with the Wt‐samples); (C), * p < 0.05, ** p < 0.01, *** p < 0.001 when comparing un‐ whentreated comparing cells with CFthe withcells thein the Wt-samples); presence of ( Ccompounds).), * p < 0.05, ** p < 0.01, *** p < 0.001 when comparing untreated cells with the cells in the presence of compounds).
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