Abstract
The voltage-dependent anion channel (VDAC) is the main interface between the cytosol and mitochondria of cells. It plays a crucial role in both mitochondrial metabolism and cell death. The main basic function of this channel is to mediate and gate the flux of small ions, metabolites, and adenosine triphosphate. Changes in its structure, and thus conformation, are expected to affect its activity and modulate the ability of cancer cells to expand. In this review, we describe a novel mechanism by which mitochondria of cells in hypoxia, a low level of oxygen, protects from apoptosis. In hypoxia, some mitochondria become enlarged due to hyperfusion. These mitochondria possess a truncated form of VDAC1 (VDAC1-ΔC), which is linked to the higher metabolic capacity and the greater resistance to cell death of hypoxic cells. However, not all of the VDAC1 protein is truncated, but the amount of the full-length form is diminished compared to the amount in normoxic cells. First, we describe how such a decrease effects cell proliferation, respiration, glycolysis, and other processes. Second, we report on a novel mitochondrial-endolysosomal crosstalk that leads to VDAC1 truncation. By pharmacological targeting of VDAC1-ΔC, the production of energy could be turned off and the sensitivity to cell death restored. This could counteract the favorable microenvironment that gives cancer cells a growth advantage and thereby disrupts the balance between life and death, which is controlled by VDAC1.
Highlights
Mitochondria have evolved over time to take on a symbiotic relationship within eukaryotic cells to produce adenosine triphosphate (ATP) through activation of the electron transport chain [1]
Functional benefits of hypoxia include epigenetic modifications, tumor vascularization, modified metabolism, signaling of metastasis, invasion and extravasation, cancer stemness, and innate immune activation, News about VDAC1 in Hypoxia all of which are under the control of complex molecular pathways driven by the transcription factor the hypoxia-inducible factor (HIF) [3, 4]
To counterbalance mitochondrial generation of reactive oxygen species (ROS) that interfere with cell survival, HIF-1 activates pyruvate dehydrogenase kinase (PDK1) to block the conversion of pyruvate to acetyl CoA resulting in decreased flux through the tricarboxylic acid (TCA) cycle [7, 8]
Summary
Mitochondria have evolved over time to take on a symbiotic relationship within eukaryotic cells to produce adenosine triphosphate (ATP) through activation of the electron transport chain [1]. We highlight a new hypoxic mechanism that modulates the amount (decrease) and structure (a cleaved form lacking its C-terminus) of the most abundant protein of the outer mitochondrial membrane [12], the voltage-dependent anion channel (VDAC), which profoundly impacts cancer cell proliferation and survival. Voltage-dependent anion channel plays a key role in both mitochondrial metabolism and cell death, acting as a convergent point of control [13, 14].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
