Targeting the Multiple Physiologic Roles of VDAC With Steroids and Hydrophobic Drugs

Abstract

There is accumulating evidence that endogenous steroids and non-polar drugs are involved in the regulation of mitochondrial physiology. Many of these hydrophobic compounds interact with the Voltage Dependent Anion Channel (VDAC). This major metabolite channel in the mitochondrial outer membrane (MOM) regulates the exchange of ions and water-soluble metabolites, such as ATP and ADP, across the MOM, thus governing mitochondrial respiration. Proteomics and biochemical approaches together with molecular dynamics simulations have identified an impressively large number of non-polar compounds, including endogenous, able to bind to VDAC. These findings have sparked speculation that both natural steroids and synthetic hydrophobic drugs regulate mitochondrial physiology by directly affecting VDAC ion channel properties and modulating its metabolite permeability. Here we evaluate recent studies investigating the effect of identified VDAC-binding natural steroids and non-polar drugs on VDAC channel functioning. We argue that while many compounds are found to bind to the VDAC protein, they do not necessarily affect its channel functions in vitro. However, they may modify other aspects of VDAC physiology such as interaction with its cytosolic partner proteins or complex formation with other mitochondrial membrane proteins, thus altering mitochondrial function.

Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins

“…This membrane is highly permeable to cations, anions, and molecules with molecular weights < 5 kDa due to the presence of large conductance channels. These channels, formed by voltage-dependent anion channel proteins (VDACs), allow for the exchange of Ca 2+ and small molecules by concentration gradients [ 2 , 43 , 44 , 45 , 46 , 47 ]. They not only regulate transport of Ca 2+ from the cytoplasm into the intermembrane space (IMS), but are additionally engaged in the mediation of cellular metabolism by transporting ATP and other small metabolites across the OMM [ 12 , 48 ].…”

“…It has been proposed to work as the principal metabolite transport system across the OMM, and had also been proposed to serve as the interconnection point between the OMM and IMM [ 50 ]. Later, three different VDAC isoforms were identified: VDAC1, VDAC2, and VDAC3 [ 2 , 44 , 47 , 51 ].…”

“…As demonstrated by Checchetto et al [ 58 ], VDAC3 isoforms demonstrate different electrophysiological properties compared with those of VDAC1 and VDAC2. In the context of their structural/functional characteristics, VDAC1, VDAC2, and VDAC3 have some similarities; at the same time, they exhibit different physiological functions regarding their interaction with cytosolic proteins and other mitochondrial proteins [ 2 , 47 , 57 , 59 ]. Furthermore, only limited information is available regarding the potential functions of VDAC2 and VDAC3 for the influx of Ca 2+ [ 43 , 59 , 60 ].…”

“…The complex consists of several subunits, including transmembrane core components and regulatory subunits that are associated with the membrane. The core components of the MCU multi-protein complex (see Box 2 for details) are comprised of: (a) core protein components: Mitochondrial Ca 2+ Uniporter (MCU), a MCU dominant negative beta subunit (MCUb), and Essential MCU REgulator (EMRE); and (b) membrane associated regulatory components: mitochondrial Ca 2+ uptake protein 1–3 (MICU1–3) and Mitochondrial Ca 2+ Uniporter Regulator 1 (MCUR1) [ 12 , 13 , 23 , 42 , 47 , 68 , 69 , 70 , 71 , 72 ]. Solute Carrier 25A23 (SLC25A23)) was initially identified as an essential component of MCU, however, it is currently under debate whether SLC25A23 is an component of MCU or whether it influences MCU indirectly [ 13 , 42 , 73 ].…”

“…MCU (mitochondrial Ca 2+ uniporter, previously known as CCDC109a, 40 kDa) is a key core component of the complex. It is encoded by a highly conservative MCU gene and is present in virtually all eukaryotic organisms [ 10 , 13 , 47 ]. MCU can be found in multiple states, and it consists of two coiled-coil domains (CC) and two transmembrane domains connected via a short loop (9 amino acid residues) containing a highly conserved DIME motif [ 42 , 65 , 66 ].…”