Abstract
VDAC (voltage-dependent anion selective channel) proteins, also known as mitochondrial porins, are the most abundant proteins of the outer mitochondrial membrane (OMM), where they play a vital role in various cellular processes, in the regulation of metabolism, and in survival pathways. There is increasing consensus about their function as a cellular hub, connecting bioenergetics functions to the rest of the cell. The structural characterization of VDACs presents challenging issues due to their very high hydrophobicity, low solubility, the difficulty to separate them from other mitochondrial proteins of similar hydrophobicity and the practical impossibility to isolate each single isoform. Consequently, it is necessary to analyze them as components of a relatively complex mixture. Due to the experimental difficulties in their structural characterization, post-translational modifications (PTMs) of VDAC proteins represent a little explored field. Only in recent years, the increasing number of tools aimed at identifying and quantifying PTMs has allowed to increase our knowledge in this field and in the mechanisms that regulate functions and interactions of mitochondrial porins. In particular, the development of nano-reversed phase ultra-high performance liquid chromatography (nanoRP-UHPLC) and ultra-sensitive high-resolution mass spectrometry (HRMS) methods has played a key role in this field. The findings obtained on VDAC PTMs using such methodologies, which permitted an in-depth characterization of these very hydrophobic trans-membrane pore proteins, are summarized in this review.
Highlights
The experimental 3D structures of mouse and human VDAC1 isoform have been determined using X-ray crystallography and NMR [5,6,7]. These analyses revealed a structure constituted by 19 β-strands arranged to form a trans-membrane β-barrel and by a region containing α-helix at the N-terminus of the protein
The location in the outer mitochondrial membrane (OMM) allows the VDAC proteins to act as anchor points for diverse sets of molecules that interact with mitochondria
The mammalian proteome is vastly more complex than the related genome. The reasons for this difference reside both in the molecular mechanisms that allow a single gene to encode for multiple proteins and in the post-translational modifications (PTMs) which represent a wide range of chemical changes that proteins can undergo after synthesis
Summary
VDAC (voltage-dependent anion selective channel) proteins, known as mitochondrial porins, are the most abundant proteins of the outer mitochondrial membrane (OMM) where they play a vital role in various cellular processes, in the regulation of metabolism, and in survival pathways. The location in the OMM allows the VDAC proteins to act as anchor points for diverse sets of molecules that interact with mitochondria In this way, VDACs are able to mediate and regulate the integration of mitochondrial functions with cellular activities. In AD post-mortem brains, in neuroblastoma cells and in an AD mouse model, a direct association was demonstrated between VDAC1, its N-terminal region, and hyper-phosphorylated Tau and with amyloid beta (Aβ), both in its monomeric and oligomeric forms [31] These interactions can have a dramatic effect on mitochondrial functions in AD neuron because they block the PTP formation, disrupt the transport of mitochondrial proteins and metabolites, and impair gating, conductance, and physiological interactome of VDACs [32]. The VDAC3 isoform is associated with cytosolic proteins as tubulins and cytoskeletal proteins, stress sensors, chaperones, and proteasome components, redoxmediating enzymes such as protein disulfide isomerase [39]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
