TY - JOUR T1 - ATP synthase K<sup>+</sup>- and H<sup>+</sup>-flux drive ATP synthesis and enable mitochondrial K<sup>+</sup>-uniporter function JF - bioRxiv DO - 10.1101/355776 SP - 355776 AU - Magdalena Juhaszova AU - Evgeny Kobrinsky AU - Dmitry B. Zorov AU - H. Bradley Nuss AU - Yael Yaniv AU - Kenneth W. Fishbein AU - Rafael de Cabo AU - Lluis Montoliu AU - Sandra B. Gabelli AU - Miguel A. Aon AU - Sonia Cortassa AU - Steven J. Sollott Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/06/26/355776.abstract N2 - We show that mammalian ATP synthase (F1Fo) utilizes the ion gradient energy not only of H+ but also of K+ to make ATP with the relative permeability of H+:K+ at ~106:1. F1Fo can be upregulated to increase the total ion-flux (at constant H+:K+) against a constant load without slip or leak, via the IF1-mediated increase in chemo-mechanical efficiency of F1Fo regulated by endogenous survival-related proteins, Bcl-xL and Mcl-1, and synthetic small molecules, diazoxide and pinacidil. Increasing ATP synthesis driven by K+- and H+-influx through Fo provides a simple way for F1Fo to operate as a primary mitochondrial K+-uniporter to regulate matrix osmotic balance matching metabolic energy supply with demand. This essential mitochondrial homeostatic mechanism also enables F1Fo to function as a recruitable mitochondrial KATP-channel, whereby triggered increases of mitochondrial K+-influx and matrix-volume upregulate the signal cascade resulting in desensitization of the permeability transition pore, enhancing cell survival during ischemia-reperfusion injury. ER -