158Starting from 1961, two models for transforma tion of the energy of oxidation reactions in mito chondria have been discussed in the literature. The model of Mitchell [1] implies that the multienzyme phosphorylation system can work in a dissociated form, while the other model (by Williams) considers a supercomplex [2].We have earlier demonstrated that the phosphory lation system is able to function in both modes, corre sponding to two structural states of mitochondria [3]. The operation modes of the phosphorylating system are provided by the system of mitochondrial volume regulation [4,5].In hypotonic media under conditions of low amplitude mitochondrial swelling, the Williams model considers protons (unstably bound to the membrane supercomplex as Brønsted acids) as a substrate for ATP synthase.In 1976, we demonstrated the possibility to use a Brønsted acid as a substrate for ATP synthase using a model system. In these experiments, ATP synthase was sorbed at the octane-water interface. In this sys tem, ATP synthesis was observed in the presence of ADP and phosphate, and the gradient of a Brønsted acid (pentachlorophenol) at the octane-water inter face was used as a source of energy; the gradient was created by adding pentachlorophenol to the octane phase [6].On the bilayer membrane, we have found the cata lysts that selectively accelerate dissociation of Brøn sted acids [7]. This allowed us to find [8] that a non equilibrium fraction of Brønsted acids with excess free energy was formed on the surface of mitoplasts (mito chondria without the outer membrane), provided that H + pumps function.The goal of this work was to prove the formation of Brønsted acids during ATP synthesis on the mito chondrial membranes.A tightly joining of the cristae (Figs. 1 and 2) and, correspondingly, the joining of the outer and inner membranes should be expected. In this process, a two membrane structure of mitoplasts is formed of the outer and inner membranes. Since the outer mem brane is well permeable ("transparent") for hydrogen ions in course of proton pumping, this structure should function as an integral whole interacting with hydrogen ions, possessing excess free energy (accord ing to the scheme in Fig. 1b).We have earlier demonstrated that the measure ment of surface ζ potential (using a Zetasizer Nano ZS device) of mitoplasts can be efficiently used for detecting formation of nonequilibrium Brønsted acids in functional states [8].To selectively accelerate dissociation of mem brane bound Brønsted acids, possessing excess free energy, we increased the concentration of catalyst (HEPES) [7].The measurements were performed in the media with a tonicity of 350 and 120 mOsm. In this experi ment, we compared the measured ζ potential on the surface of functional mitochondria during ATP syn thesis under isotonic and hypotonic conditions. The experiments conducted under hypotonic conditions have demonstrated (Table 1) that the changes in ζ potential on the mitochondrial surface regularly cor relate with the changes in ζ potential on t...

Introduction: Genome Wide Association Studies (GWAS) have identified several genes associated with schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. Additionally, products of GWAS genes interact with neuronal factors coded by genes lacking association, such that this interaction may confer risk for specific phenotypes of this brain disorder. In this regard, FXR1 (Fragile-X mental-retardation-syndrome-related 1) gene has been GWAS associated with SCZ. FXR1 protein is regulated by Glycogen Synthase Kinase-3 (GSK3 ), which has been implicated in pathophysiology of SCZ and response to Antipsychotics (APs). rs496250 and rs12630592, two eQTLs of FXR1 and GSK3 respectively, interact on emotion stability and amygdala/PFC activity during emotion processing. These two phenotypes are associated with Negative Symptoms (NS) of SCZ suggesting that the interaction between these SNPs may also affect NS severity and responsiveness to medication. Methods:To test this hypothesis, in two independent samples of patients with SCZ, we investigated rs496250 by rs12630592 interaction on NS severity and response to APs. We also tested a putative link between APs administration and fxr1 expression, as already reported for GSK3 expression. Results:We found that rs496250 and rs12630592 interact on NS severity. We also found evidence suggesting interaction of these polymorphisms also on response to APs. This interaction was not present when looking at positive and general psychopathology scores. Furthermore, chronic olanzapine administration led to a reduction of FXR1 expression in mouse frontal cortex. Discussion: Our findings suggest that, like GSK3 , FXR1 is affected by APs while shedding new light on the role of the FXR1/GSK3 pathway for NS of SCZ.

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