**3.3. Vimentin and plectin**

is even 2 orders of magnitude less than the flux of small ions through VDAC in the closed state. However, when VDAC closes, the transition of major anionic metabolites (as creatine phosphate, ATP, ADP, Pi, and respiratory substrates) is prevented [19]. A number of papers have been published that confirm the VDAC conductance regulation by several factors contributing to the explanation of mitochondria dysfunction and affection by the energy metabolism of cells.

**3. Physiological implication of VDAC affection by membrane bound**

It has been shown that the disruption of mitochondrial functions is linked to the occurrence of mutations in genes encoding various types of intermediate filament proteins. In humans, the different morphology, distribution, and function of mitochondria in patients with neurological disorder [20, 21], types of myopathies [22, 23], or epidermolysis bullosa simplex [24] were documented. The cytoskeleton proteins as tubulin, desmin, vimentin, and plectin have been found to interact with mitochondrial outer membrane, where they are involved in the ATP/ADP transmission control through VDAC, thus mediating or influencing mitochondrial functions.

Tubulin binds with high affinity to cellular membranes, and bound to mitochondrial membranes represent ~ 2% of total cellular tubulin [25]. It is important for ensuring intracellular transport and DNA segregation in cell division. Rostovtseva et al. [19] have found induction of fast, reversible blockade of VDAC conductance by tubulin at nanomolar concentration in 1–100 ms range. Closing occurs in concentration-dependent manner and negative potential as low as 5 mV. The type of VDAC, phosphorylation level, and membrane lipid composition have an impact on VDAC blocking. Change in channel selectivity in blocked state results in impermeability to ATP [26]. The restriction of ATP/ADP and other respiratory substrates fluxes leads to reduction of oxidative phosphorylation and promotion of apoptosis. Therefore, signals that enhance VDACtubulin binding by kinase-regulated phosphorylating VDAC or by increasing the concentration

of available free tubulin in the cytosol would reduce mitochondrial respiration [27].

One other regulating mitochondria affinity to ADP and oxygen consumption through direct binding to VDAC is the muscle-specific intermediate filament protein, desmin. The function of desmin is to form a three-dimensional scaffold that interconnects the contractile apparatus to the nucleus, cellular organelles, and the sarcolemma [28]. Proximity of sarcoplasmic reticulum and mitochondria by desmin scaffold allows facilitation of direct protein and metabolite targeting to mitochondria [29–31]. Interaction of desmin with contact sites (VDAC, adenine nucleotide translocator (ANT) and mitochondrial contact site complex) affects mitochondrial permeability transition pore (mtPTP) behavior and respiratory function [32, 33]. Studies on mice have shown that desmin deficiency leads to development of skeletal and myocardial defects associated with a deteriorated structure and function of mitochondria [22, 34].

**proteins**

254 Mitochondrial Diseases

**3.1. Tubulin**

**3.2. Desmin**

Association of vimentin with mitochondria increases mitochondrial membrane potential and has an important function in controlling the production of ATP to various sites in the cytoplasm [40]. As a possible mechanism of action, the similarity of the mitochondrial binding site on vimentin with the domains targeting outer mitochondrial membrane is reported. The domains interact with the VDAC, increasing its permeability for several negatively charged compounds (such as pyruvate, succinate, ADP, etc.), thus compensating decreasing membrane potential effects of hexokinase [41], or tubulin. A study by Winter et al. [42] suggests that plectin 1b also plays an important role in regulating mitochondrial outer membrane permeability to ADP and ATP through VDAC.
