Modulatory Effect of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) on the 2-Oxoglutarate Mitochondrial Carrier

The 2-oxoglutarate carrier (OGC), pivotal in cellular metabolism, facilitates the exchange of key metabolites between mitochondria and cytosol. This study explores the influence of NADPH on OGC transport activity using proteoliposomes. Experimental data revealed the ability of NADPH to modulate the...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2024-11, Vol.29 (21), p.5154
Main Authors: Spagnoletta, Anna, Miniero, Daniela Valeria, Gambacorta, Nicola, Oppedisano, Francesca, De Grassi, Anna, Nicolotti, Orazio, Pierri, Ciro Leonardo, De Palma, Annalisa
Format: Article
Language:English
Subjects:
Apoptosis
Biological Transport
Dehydrogenases
Diabetes
Enzymes
Ethylenediaminetetraacetic acid
Homeostasis
isocitrate/oxoglutarate shuttle
Ketoglutaric Acids - metabolism
kinetic analysis
Kinetics
Membrane Transport Proteins
Metabolism
Metabolites
Mitochondria
Mitochondria - metabolism
mitochondrial transport
molecular docking
Molecular Docking Simulation
NADP - metabolism
NADPH regulation
Neurodegeneration
Niacinamide
Oxidation-Reduction
Oxidative stress
oxoglutarate carrier
Phosphates
Physiological aspects
Physiology
Purines
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Summary:The 2-oxoglutarate carrier (OGC), pivotal in cellular metabolism, facilitates the exchange of key metabolites between mitochondria and cytosol. This study explores the influence of NADPH on OGC transport activity using proteoliposomes. Experimental data revealed the ability of NADPH to modulate the OGC activity, with a significant increase of 60% at 0.010 mM. Kinetic analysis showed increased Vmax and a reduction in Km for 2-oxoglutarate, suggesting a direct regulatory role. Molecular docking pointed to a specific interaction between NADPH and cytosolic loops of OGC, involving key residues such as K206 and K122. This modulation was unique in mammalian OGC, as no similar effect was observed in a plant OGC structurally/functionally related mitochondrial carrier. These findings propose OGC as a responsive sensor for the mitochondrial redox state, coordinating with the malate/aspartate and isocitrate/oxoglutarate shuttles to maintain redox balance. The results underscore the potential role of OGC in redox homeostasis and its broader implications in cellular metabolism and oxidative stress responses.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules29215154