The Voltage-Dependent Anion Channel 1, or VDAC1, is a protein found across nearly all eukaryotic cells, from yeast to humans. It resides primarily within the outer mitochondrial membrane, serving as a gateway between the cell’s main compartment, the cytosol, and the mitochondria. VDAC1 controls the movement of various substances into and out of mitochondria. Its role as a metabolic exchange point makes it a continuously studied component of cellular biology.
Core Functions of VDAC1
VDAC1 operates as a channel that regulates the passage of small molecules and ions across the outer mitochondrial membrane. This includes metabolites such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), pyruvate, and citrate, all involved in energy metabolism. The controlled diffusion of these substances is important for the cell’s energy production. VDAC1 facilitates the exchange of ATP, generated within the mitochondria, to the cytosol for cellular activities, while allowing ADP to enter the mitochondria for re-phosphorylation.
This exchange ensures mitochondria produce energy and maintain metabolic balance. VDAC1 is the most abundant protein in the outer mitochondrial membrane, allowing molecules up to approximately 5,000 daltons to pass. Its permeability can be influenced by changes in membrane potential, switching VDAC1 between an “open” or high-conducting state and a “closed” or low-conducting state.
VDAC1’s Role in Cellular Regulation
Beyond its direct role in metabolite transport, VDAC1 participates in broader cellular regulatory processes, including programmed cell death, known as apoptosis. It influences the release of pro-apoptotic proteins, such as cytochrome c, from the mitochondrial intermembrane space into the cytosol, which can trigger cell death. This occurs partly through VDAC1’s ability to undergo conformational changes and oligomerization, forming larger channels that facilitate the passage of these proteins.
VDAC1 also plays a part in calcium signaling, mediating the transport of calcium ions into and out of mitochondria. Intramitochondrial calcium levels are important for regulating energy metabolism by enhancing enzymes in the tricarboxylic acid cycle. The protein’s open or closed states influence these processes, and its interactions with various regulatory proteins, including members of the Bcl-2 family, modulate its function in cell survival and stress responses.
VDAC1 and Disease
Dysregulation or altered expression of VDAC1 is implicated in several diseases, particularly cancer and neurodegenerative disorders. In cancer, tumor cells often exhibit altered metabolism, relying heavily on glycolysis even in the presence of oxygen, a phenomenon known as the Warburg effect. VDAC1 contributes to this by interacting with hexokinase, which gains preferential access to mitochondrial ATP, fueling the high glycolytic rate characteristic of many cancer cells. Increased VDAC1 levels are observed in various human cancer cell lines, and its overexpression can inhibit apoptosis, contributing to chemotherapy resistance.
In neurodegenerative diseases like Alzheimer’s and Parkinson’s, VDAC1’s impact on mitochondrial function and cell survival is significant. In Alzheimer’s disease, VDAC1 expression levels can be enhanced, and its interaction with hexokinase may be reduced. This can increase VDAC1’s tendency to form oligomers, which promotes programmed cell death and contributes to neuronal loss. Similarly, in Parkinson’s disease, α-synuclein, a protein involved in the disease, has been found to associate with VDAC1. VDAC1’s involvement in mitochondrial dysfunction and altered calcium homeostasis in these conditions is relevant to disease pathology.
Targeting VDAC1 for Health
Given its role in cellular metabolism and cell death pathways, VDAC1 is a potential target for therapeutic interventions. Scientists are exploring ways to modulate VDAC1 activity to develop new treatments for diseases where its function is altered. For instance, specific inhibitors of VDAC1 oligomerization, such as VBIT-3 and VBIT-4, are being investigated for their potential to inhibit apoptosis in disorders like neurodegenerative and cardiovascular diseases.
Compounds like AKOS-22 can directly interact with VDAC1 to inhibit its oligomerization and subsequent apoptosis, offering protection against mitochondrial dysfunction. VDAC1’s interaction with hexokinase in cancer cells presents an opportunity to disrupt the Warburg effect, potentially sensitizing tumor cells to treatment. The potential of VDAC1 as a diagnostic biomarker is also being explored, as its expression levels or modifications could indicate disease states or progression.