Decoding Cancer through Silencing the Mitochondrial Gatekeeper VDAC1.

Mitochondria serve as central hubs for regulating numerous cellular processes that include metabolism, apoptosis, cell cycle progression, proliferation, differentiation, epigenetics, immune signaling, and aging. The voltage-dependent anion channel 1 (VDAC1) functions as a crucial mitochondrial gatekeeper, controlling the flow of ions, such as Ca, nucleotides, and metabolites across the outer mitochondrial membrane, and is also integral to mitochondria-mediated apoptosis. VDAC1 functions in regulating ATP production, Ca homeostasis, and apoptosis, which are essential for maintaining mitochondrial function and overall cellular health.

Correction: Pittala et al. The VDAC1-based R-Tf-D-LP4 Peptide as a Potential Treatment for Diabetes Mellitus. 2020, , 481.

In the original publication [...

Elevated serum mtDNA in COVID-19 patients is linked to SARS-CoV-2 envelope protein targeting mitochondrial VDAC1, inducing apoptosis and mtDNA release.

Mitochondria dysfunction is implicated in cell death, inflammation, and autoimmunity. During viral infections, some viruses employ different strategies to disrupt mitochondria-dependent apoptosis, while others, including SARS-CoV-2, induce host cell apoptosis to facilitate replication and immune system modulation. Given mitochondrial DNAs (mtDNA) role as a pro-inflammatory damage-associated molecular pattern in inflammatory diseases, we examined its levels in the serum of COVID-19 patients and found it to be high relative to levels in healthy donors.

VDAC1-Based Peptides as Potential Modulators of VDAC1 Interactions with Its Partners and as a Therapeutic for Cancer, NASH, and Diabetes.

This review presents current knowledge related to the voltage-dependent anion channel-1 (VDAC1) as a multi-functional mitochondrial protein that acts in regulating both cell life and death. The location of VDAC1 at the outer mitochondrial membrane (OMM) allows control of metabolic cross-talk between the mitochondria and the rest of the cell, and also enables its interaction with proteins that are involved in metabolic, cell death, and survival pathways. VDAC1's interactions with over 150 proteins can mediate and regulate the integration of mitochondrial functions with cellular activities.

Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.

Metabolic enzymes can adapt during energy stress, but the consequences of these adaptations remain understudied. Here, we discovered that hexokinase 1 (HK1), a key glycolytic enzyme, forms rings around mitochondria during energy stress. These HK1-rings constrict mitochondria at contact sites with the endoplasmic reticulum (ER) and mitochondrial dynamics protein (MiD51).

Silencing the Mitochondrial Gatekeeper VDAC1 as a Potential Treatment for Bladder Cancer.

The strategy for treating bladder cancer (BC) depends on whether there is muscle invasion or not, with the latter mostly treated with intravesical therapy, such as with bacillus Calmette-Guérin (BCG). However, BCG treatment is unsuccessful in 70% of patients, who are then subjected to radical cystectomy. Although immune-checkpoint inhibitors have been approved as a second-line therapy for a subset of BC patients, these have failed to meet primary endpoints in clinical trials.

Interaction of SMAC with a survivin-derived peptide alters essential cancer hallmarks: Tumor growth, inflammation, and immunosuppression.

Second mitochondrial-derived activator of caspase (SMAC), also known as direct inhibitor of apoptosis-binding proteins with low pI (Diablo), is known as a pro-apoptotic mitochondrial protein released into the cytosol in response to apoptotic signals. We recently reported SMAC overexpression in cancers as essential for cell proliferation and tumor growth due to non-apoptotic functions, including phospholipid synthesis regulation. These functions may be associated with its interactions with partner proteins.

Overexpression of the mitochondrial anti-viral signaling protein, MAVS, in cancers is associated with cell survival and inflammation.

Mitochondrial anti-viral signaling protein (MAVS) plays an important role in host defense against viral infection via coordinating the activation of NF-κB and interferon regulatory factors. The mitochondrial-bound form of MAVS is essential for its anti-viral innate immunity. Recently, tumor cells were proposed to mimic a viral infection by activating RNA-sensing pattern recognition receptors.

Pro-Apoptotic and Anti-Cancer Activity of the Vernonanthura Nudiflora Hydroethanolic Extract.

The mitochondrial voltage-dependent anion channel 1 (VDAC1) protein is involved in several essential cancer hallmarks, including energy and metabolism reprogramming and apoptotic cell death evasion. In this study, we demonstrated the ability of hydroethanolic extracts from three different plants, (Vern), (Bac), and (Pla), to induce cell death. We focused on the most active Vern extract.

Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer's disease protects against mitochondrial dysfunction and mitigates brain pathology.

Background: Alzheimer's disease (AD) exhibits mitochondrial dysfunctions associated with dysregulated metabolism, brain inflammation, synaptic loss, and neuronal cell death. As a key protein serving as the mitochondrial gatekeeper, the voltage-dependent anion channel-1 (VDAC1) that controls metabolism and Ca homeostasis is positioned at a convergence point for various cell survival and death signals. Here, we targeted VDAC1 with VBIT-4, a newly developed inhibitor of VDAC1 that prevents its pro-apoptotic activity, and mitochondria dysfunction.

The Multicellular Effects of VDAC1 N-Terminal-Derived Peptide.

The mitochondrial voltage-dependent anion channel-1 (VDAC1) protein functions in a variety of mitochondria-linked physiological and pathological processes, including metabolism and cell signaling, as well as in mitochondria-mediated apoptosis. VDAC1 interacts with about 150 proteins to regulate the integration of mitochondrial functions with other cellular activities. Recently, we developed VDAC1-based peptides that have multiple effects on cancer cells and tumors including apoptosis induction.

Non-apoptotic activity of the mitochondrial protein SMAC/Diablo in lung cancer: Novel target to disrupt survival, inflammation, and immunosuppression.

Mitochondrial SMAC/Diablo induces apoptosis by binding the inhibitor of apoptosis proteins (IAPs), thereby activating caspases and, subsequently, apoptosis. Previously, we found that despite its pro-apoptotic activity, SMAC/Diablo is overexpressed in cancer, and demonstrated that in cancer it possesses new essential and non-apoptotic functions that are associated with regulating phospholipid synthesis including modulating mitochondrial phosphatidylserine decarboxylase activity. Here, we demonstrate additional functions for SMAC/Diablo associated with inflammation and immunity.

Targeting the Mitochondrial Protein VDAC1 as a Potential Therapeutic Strategy in ALS.

Impaired mitochondrial function has been proposed as a causative factor in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), caused by motor neuron degeneration. Mutations in superoxide dismutase (SOD1) cause ALS and SOD1 mutants were shown to interact with the voltage-dependent anion channel 1 (VDAC1), affecting its normal function. VDAC1 is a multi-functional channel located at the outer mitochondrial membrane that serves as a mitochondrial gatekeeper controlling metabolic and energetic crosstalk between mitochondria and the rest of the cell and it is a key player in mitochondria-mediated apoptosis.

Silencing VDAC1 to Treat Mesothelioma Cancer: Tumor Reprograming and Altering Tumor Hallmarks.

Mesothelioma, an aggressive cancer with a poor prognosis, is linked to asbestos exposure. However, carbon nanotubes found in materials we are exposed to daily can cause mesothelioma cancer. Cancer cells reprogram their metabolism to support increased biosynthetic and energy demands required for their growth and motility.

Adverse Effects of Metformin From Diabetes to COVID-19, Cancer, Neurodegenerative Diseases, and Aging: Is VDAC1 a Common Target?

Metformin has been used for treating diabetes mellitus since the late 1950s. In addition to its antihyperglycemic activity, it was shown to be a potential drug candidate for treating a range of other diseases that include various cancers, cardiovascular diseases, diabetic kidney disease, neurodegenerative diseases, renal diseases, obesity, inflammation, COVID-19 in diabetic patients, and aging. In this review, we focus on the important aspects of mitochondrial dysfunction in energy metabolism and cell death with their gatekeeper VDAC1 (voltage-dependent anion channel 1) as a possible metformin target, and summarize metformin's effects in several diseases and gut microbiota.

The role of the mitochondrial protein VDAC1 in inflammatory bowel disease: a potential therapeutic target.

Recent studies have implicated mitochondrial dysfunction as a trigger of inflammatory bowel diseases, including Crohn's disease (CD) and ulcerative colitis (UC). We have investigated the role of the mitochondria gate-keeper protein, the voltage-dependent-anion channel 1 (VDAC1), in gastrointestinal inflammation and tested the effects of the newly developed VDAC1-interacting molecules, VBIT-4 and VBIT-12, on UC induced by dextran sulfate sodium (DSS) or trinitrobenzene sulphonic acid (TNBS) in mice. VDAC1, which controls metabolism, lipids transport, apoptosis, and inflammasome activation, is overexpressed in the colon of CD and UC patients and DSS-treated mice.

VDAC1 Silencing in Cancer Cells Leads to Metabolic Reprogramming That Modulates Tumor Microenvironment.

The tumor microenvironment (TME) plays an important role in cell growth, proliferation, migration, immunity, malignant transformation, and apoptosis. Thus, better insight into tumor-host interactions is required. Most of these processes involve the metabolic reprogramming of cells.

SMAC/Diablo controls proliferation of cancer cells by regulating phosphatidylethanolamine synthesis.

SMAC/Diablo, a pro-apoptotic protein, yet it is overexpressed in several cancer types. We have described a noncanonical function for SMAC/Diablo as a regulator of lipid synthesis during cancer cell proliferation and development. Here, we explore the molecular mechanism through which SMAC/Diablo regulates phospholipid synthesis.

VDAC1 in the diseased myocardium and the effect of VDAC1-interacting compound on atrial fibrosis induced by hyperaldosteronism.

The voltage-dependent anion channel 1 (VDAC1) is a key player in mitochondrial function. VDAC1 serves as a gatekeeper mediating the fluxes of ions, nucleotides, and other metabolites across the outer mitochondrial membrane, as well as the release of apoptogenic proteins initiating apoptotic cell death. VBIT-4, a VDAC1 oligomerization inhibitor, was recently shown to prevent mitochondrial dysfunction and apoptosis, as validated in mouse models of lupus and type-2 diabetes.

Empty mesoporous silica particles significantly delay disease progression and extend survival in a mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating incurable neurological disorder characterized by motor neuron (MN) death and muscle dysfunction leading to mean survival time after diagnosis of only 2-5 years. A potential ALS treatment is to delay the loss of MNs and disease progression by the delivery of trophic factors. Previously, we demonstrated that implanted mesoporous silica nanoparticles (MSPs) loaded with trophic factor peptide mimetics support survival and induce differentiation of co-implanted embryonic stem cell (ESC)-derived MNs.