The 2-oxoglutarate/malate carrier extends the family of mitochondrial carriers capable of FA-activated proton transport

Metabolic reprogramming in cancer cells has been linked to the mitochondrial dysfunction. Recent studies have suggested the mitochondrial 2-oxoglutarate/malate carrier (OGC) as a potential target for preventing cancer progression. Although OGC is known to be a part of the malate/aspartate shuttle, its exact role in cancer metabolism remains unclear. In this study, we investigated the contribution of recombinant murine OGC to the proton transport by measuring the conductance (G m ) of planar lipid bilayer membranes reconstituted with OGC. Our results show that OGC significantly increases G m only in the presence of free fatty acids (FAs) and 2,4-dinitrophenol, demonstrating for the first time its involvement in proton transport. We found that (i) the increase in OGC activity directly correlates with the increase in the number of unsaturated bonds of FAs, and (ii) OGC substrates and inhibitors compete with FAs for the same binding site. In addition, we have identified R90 as a crucial amino acid of the binding site for FAs, ATP, 2-oxoglutarate, and malate, which is a first step towards understanding the OGC-mediated proton transport mechanism. Elucidating the contribution of OGC to the uncoupling will be crucial in the design of targeted drugs for the treatment of cancer and other metabolic diseases.