**1. Introduction**

Mitochondria are two membrane organelles present in all cells that have a nucleus. They are the energy center of the cells. Their primary role is the production of ATP in oxidative

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phosphorylation, and the basis of the aerobic oxidation is the citric acid cycle interconnection representing the final metabolic pathway of oxidation of all major nutrients to the respiratory chain where oxidation of reduced coenzymes results in ATP formation. The nutrient to be oxidized must transfer the mitochondria by means of the transporters, as pyruvate produced in glycolysis in the cytosol. After fatty acids released by hydrolysis of lipoproteins or triacylglycerols transport across the mitochondrial membranes, acetyl-CoA arising from β-oxidation enters the citric acid cycle. Similarly, amino acids or their catalytic products enter the citric acid cycle at different sites. The production of energy in mitochondria from various nutrients is controlled by the availability of the individual nutrients that a given organ or tissue can use. For example, in excess of carbohydrates, the energy is obtained from glycolysis rather than from fatty acids and amino acids. The needs for ATP produced in oxidative phosphorylation vary in different cell compartments, and therefore it is efficiently transported out of mitochondria. Through the activity of uncoupler proteins, mitochondria also regulate energy production in the form of heat. In addition to providing different forms of energy, mitochondria are involved in other important metabolic processes. In the excess of saccharides, the acetyl-CoA resulting from pyruvate is not used in the citric acid cycle but is transported to the cytosol for the synthesis of more energy-efficient reserve, triacylglycerols. When there is a lack of glucose, mitochondria provide the intermediates for gluconeogenesis, but also participate in the synthesis of various substances, such as urea, heme, and polyamines. Reactive oxygen and nitrogen species production and triggering the intrinsic apoptotic pathway are other significant functions. They synthesize proteins from their own DNA, but most mitochondrial proteins are encoded by nuclear genes. Mitochondria are the sole site for Fe-S cluster biogenesis, which is also the only fully conservative function. The diversity and importance of biochemical pathways taking place in the mitochondria require the access of substrates and transport products generated outside the mitochondria. In terms of ensuring the normal physiological functions of the mitochondria, it is therefore crucial to ensure the transfer of the substances through the mitochondrial membranes separating the organelle from the cytoplasm, thus allowing the course of these specialized metabolic processes. Therefore, the chapter is focused on the mitochondrial transport proteins, transporters of citric acid cycle intermediates, localized in mitochondrial outer and inner membrane, since their activities significantly affect the functions of mitochondria and subsequently functions of the given organ, tissues, and the whole organism.

some also exhibiting an inactivation step forming a completely continuous tunnel through a bilayer that allows for rapid conductance of many ions [3]. The third protein family are voltagedependent anion channels (VDAC), which are permanently open under physiological conditions with some evidence-based regulations [4]. VDAC is the most abundant protein of outer mitochondrial membrane (∼ 10 thousand copies per mitochondrion), whose functions in permeability of compounds between cytosol and mitochondria have been shown to be related either to physiological or pathological states [5–7]. Many cases of abnormal manifestations of mitochondria are the consequence of this type of regulation of the mitochondrial outer membrane permeability [8].

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The functions of VDAC related to four main aspects are controlling of transport of metabolites and ATP transport between mitochondria and cytoplasm, forming part of mitochondrial permeability transition pore; modulation of inner mitochondrial Ca2+ level through connection to endoplasmic reticulum calcium release channel IP3R with glucose-related protein 75 and through phosphorylation cluster sorting protein 2 (PACS2), regulating Bid of Bcl2 proapoptotic factor family-mediated apoptotic pathways; and regulation of intracellular redox substances [9]. VDAC is a way of transiting reactive oxygen species (ROS) from mitochondria to cytoplasm, though it reacts directly with the NO leading to decrease in permeability and

VDAC, mitochondrial porin, forms a barrel comprised of a transmembrane alpha helix and 13- and more transmembrane beta strands. Beta barrel encloses a channel large in diameter (~3 nm), which is permeable to molecules up to ~5 kDa in the open configuration [11]. *In vitro* studies have shown a conserved property of eukaryotic VDAC channels to adopt multiple conductance states [12]. In humans, three isoforms of VDAC (VDAC 1–3) located on chromosome 5, each of 30 kDa, are known [13]. VDAC1 and 2 have prototypic voltage gating, but VDAC2 also has a second discrete lower conductance and ion selective state. VDAC3 is not fully voltage-dependent [14], and unlike the previous two types, VDAC3 is evenly distributed [15].

The role of membrane potentials (Ψ) in the physiological regulation of VDAC conductance is considered with regard to appearance of Donnan potential across the outer membrane [16]. However, ambiguity is not confirmed due to the presence of charged macromolecules on both sides of outer membrane, and high ionic strength of intracellular environment decreasing Donnan potentials and causing closure of channels. Differences in pH across the outer membrane indicate the presence of Donnan potential of ~−40 mV, close to a gating potential for VDAC [17]. Positive and negative ΔΨ close VDAC symmetrically with half maximal closure at ±50 mV. In the open state, anions are favored over cations, but the selectivity is weak. In the closed state, VDAC becomes a cation selective pore of 1.8 nm in diameter that still conducts

, and Ca2+, as well as Cl<sup>−</sup>

lapses electrical potentials [16]. In most conductive, open state, VDAC shows significant preference especially for metabolic anions. The states of lower conductance reduce permeability to metabolic anions, thus greatly diminishing metabolite flux across the outer mitochondrial membrane [18]. The flux of charged metabolites does not significantly contribute to the membrane potential because it is confined by the internal mitochondrial membrane transport, which

, whose movement through VDAC col-

**2.1. Voltage-dependent anion channel**

inhibition of mitochondrial transition pore [10].

small cations, such as K+

, Na+
