Exploring the proton transport mechanism of the mitochondrial ADP/ATP carrier: FA‐cycling hypothesis and beyond

Abstract The mitochondrial ADP/ATP carrier (AAC, ANT), a member of the SLC25 family of solute carriers, plays a critical role in transporting purine nucleotides (ATP and ADP) as well as protons across the inner mitochondrial membrane. However, the precise mechanism and physiological significance of proton transport by ADP/ATP carrier remain unclear. Notably, the presence of uncouplers—such as long‐chain fatty acids (FA) or artificial compounds like dinitrophenol (DNP)—is essential for this process. We explore two potential mechanisms that describe ADP/ATP carrier as either (i) a proton carrier that functions in the presence of FA or DNP, or (ii) an anion transporter (FA − or DNP). In the latter case, the proton is translocated by the neutral form of FA, which carries it from the matrix to the intermembrane space (FA‐cycling hypothesis). Our recent results support this hypothesis. We describe a four‐step mechanism for the “sliding” of the FA anion from the matrix to the mitochondrial intermembrane space and discuss a possible generalization of this mechanism to other SLC25 carriers.