Mitochondrial metabolism and function are modulated by changes in matrix Ca²⁺. Small increases in the matrix Ca²⁺ stimulate mitochondrial bioenergetics, whereas excessive Ca²⁺ 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 Ca²⁺ 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_OF₁-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 Ca²⁺ overload initiates PTP opening via an ANT switch-like mechanism activated by matrix Ca²⁺ and is inhibited by extra-mitochondrial ADP. We found that encoding a heterogeneous Ca²⁺ response of at least three types of PTPs, weakly, moderately, and strongly sensitive to Ca²⁺, enabled the model to simulate Ca²⁺ 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.

Graphical abstract

中文翻译：

---

腺嘌呤核苷酸转运蛋白与线粒体肿胀之间的串扰：实验和计算方法

线粒体代谢和功能受基质 Ca ²⁺变化的调节。基质 Ca ²⁺的少量增加会刺激线粒体生物能量学，而过多的 Ca ²⁺会导致大量基质肿胀并损害线粒体的结构和功能完整性，从而导致细胞死亡。非选择性线粒体通透性转换孔 (PTP) 的持续开放是导致线粒体功能障碍和细胞死亡的线粒体 Ca ²⁺超载的主要机制。最近的研究表明存在两种或多种类型的 PTP，以及腺嘌呤核苷酸转运蛋白 (ANT) 和 F _O F ₁-ATP合酶被提议形成相互独立的PTP。在这里，我们通过应用实验和计算方法阐明了 ANT 在 PTP 开放中的作用。我们首先开发并证实了 ANT 传输机制的详细模型，包括矩阵（ANT _M）、细胞溶质（ANT _C）和转运体的孔隙（ANT _{P ）状态。}^{然后，将 ANT 模型合并到一个简单但有效的线粒体生物能学经验模型中，以确定 Ca 2+超载通过基质 Ca 2+}激活的 ANT 开关样机制启动 PTP 打开的时间点，并被额外的抑制线粒体 ADP。我们发现编码异质 Ca ²⁺至少三种类型的 PTP（对 Ca ²⁺的弱、中度和强敏感）的反应使该模型能够模拟在对充满活力的心脏线粒体群体进行大量推注后观察到的Ca ^{2+释放动力学。}因此，这项研究证明了 ANT 在 PTP 门控中的潜在作用，并提出了一种控制 PTP 现象的神秘性质的新机制。

图形概要