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. © 2024 by the authors.

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