Crosstalk between adenine nucleotide transporter and mitochondrial swelling: experimental and computational approaches.

Mitochondrial metabolism and function are modulated by changes in matrix Ca 2+ . Small increases in the matrix Ca 2+ stimulate mitochondrial bioenergetics, whereas excessive Ca 2+ leads to cell death by causing massive matrix swelling and impairing the structural and functional integrity of mitochondria. Sustained opening of the non-selective mitochondrial permeability transition pores (PTP) is the main mechanism responsible for mitochondrial Ca 2+ overload that leads to mitochondrial dysfunction and cell death. Recent studies suggest the existence of two or more types of PTP, and adenine nucleotide translocator (ANT) and F O F 1 -ATP synthase were proposed to form the PTP independent of each other. Here, we elucidated the role of ANT in PTP opening by applying both experimental and computational approaches. We first developed and corroborated a detailed model of the ANT transport mechanism including the matrix (ANT M ), cytosolic (ANT C ), and pore (ANT P ) states of the transporter. Then, the ANT model was incorporated into a simple, yet effective, empirical model of mitochondrial bioenergetics to ascertain the point when Ca 2+ overload initiates PTP opening via an ANT switch-like mechanism activated by matrix Ca 2+ and is inhibited by extra-mitochondrial ADP. We found that encoding a heterogeneous Ca 2+ response of at least three types of PTPs, weakly, moderately, and strongly sensitive to Ca 2+ , enabled the model to simulate Ca 2+ release dynamics observed after large boluses were administered to a population of energized cardiac mitochondria. Thus, this study demonstrates the potential role of ANT in PTP gating and proposes a novel mechanism governing the cryptic nature of the PTP phenomenon.