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. We question how the same drug can act on diseases with opposite characteristics, such as increasing apoptotic cell death in cancer, while inhibiting it in neurodegenerative diseases. Interestingly, metformin’s adverse effects in many diseases all show VDAC1 involvement, suggesting that it is a common factor in metformin-affecting diseases. The findings that metformin has an opposite effect on various diseases are consistent with the fact that VDAC1 controls cell life and death, supporting the idea that it is a target for metformin.

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Bcl-2 Family of Proteins: Life-or-Death Switch in Mitochondria

Bioscience Reports ◽

10.1023/a:1016061006256 ◽

2002 ◽

Vol 22 (1) ◽

pp. 47-58 ◽

Cited By ~ 71

Author(s):

Yoshihide Tsujimoto

Keyword(s):

Cell Death ◽

Mitochondrial Membrane ◽

Apoptotic Cell ◽

Regulatory Protein ◽

Family Members ◽

Anion Channel ◽

Permeability Transition ◽

Outer Mitochondrial Membrane ◽

Voltage Dependent Anion Channel ◽

Membrane Barrier

An increase in the permeability of outer mitochondrial membrane is central to apoptotic cell death, and results in the release of several apoptogenic factors such as cytochrome c into the cytoplasm to activate downstream destructive programs. The voltage-dependent anion channel (VDAC or mitochondrial porin) plays an essential role in disrupting the mitochondrial membrane barrier and is regulated directly by members of the Bcl-2 family proteins. Anti-apoptotic Bcl-2 family members interact with and close the VDAC, whereas some, but not all, proapoptotic members interact with VDAC to open protein-conducting pore through which apoptogenic factors pass. Although the VDAC is involved directly in breaking the mitochondrial membrane barrier and is a known component of the permeability transition pore complex, VDAC-dependent increase in outer membrane permeability can be independent of the permeability transition event such as mitochondrial swelling followed by rupture of the outer mitochondrial membrane. VDAC interacts not only with Bcl-2 family members but also with proteins such as gelsolin, an actin regulatory protein, and appears to be a convergence point for a variety of cell survival and cell death signals.

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MAVS Regulates Apoptotic Cell Death by Decreasing K48-Linked Ubiquitination of Voltage-Dependent Anion Channel 1

Molecular and Cellular Biology ◽

10.1128/mcb.00030-13 ◽

2013 ◽

Vol 33 (16) ◽

pp. 3137-3149 ◽

Cited By ~ 39

Author(s):

Kai Guan ◽

Zirui Zheng ◽

Ting Song ◽

Xiang He ◽

Changzhi Xu ◽

...

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Anion Channel ◽

Apoptotic Cell Death ◽

Type I ◽

Voltage Dependent Anion Channel ◽

Voltage Dependent ◽

Consequent Reduction ◽

Mitochondrial Antiviral Signaling ◽

Induced Apoptosis

The mitochondrial antiviral signaling protein MAVS (IPS-1, VISA, or Cardif) plays an important role in the host defense against viral infection by inducing type I interferon. Recent reports have shown that MAVS is also critical for virus-induced apoptosis. However, the mechanism of MAVS-mediated apoptosis induction remains unclear. Here, we show that MAVS binds to voltage-dependent anion channel 1 (VDAC1) and induces apoptosis by caspase-3 activation, which is independent of its role in innate immunity. MAVS modulates VDAC1 protein stability by decreasing its degradative K48-linked ubiquitination. In addition, MAVS knockout mouse embryonic fibroblasts (MEFs) display reduced VDAC1 expression with a consequent reduction of the vesicular stomatitis virus (VSV)-induced apoptosis response. Notably, the upregulation of VDAC1 triggered by VSV infection is completely abolished in MAVS knockout MEFs. We thus identify VDAC1 as a target of MAVS and describe a novel mechanism of MAVS control of virus-induced apoptotic cell death.

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In self-defence: hexokinase promotes voltage-dependent anion channel closure and prevents mitochondria-mediated apoptotic cell death

Biochemical Journal ◽

10.1042/bj20031465 ◽

2004 ◽

Vol 377 (2) ◽

pp. 347-355 ◽

Cited By ~ 259

Author(s):

Heftsi AZOULAY-ZOHAR ◽

Adrian ISRAELSON ◽

Salah ABU-HAMAD ◽

Varda SHOSHAN-BARMATZ

Keyword(s):

Cell Death ◽

Cell Survival ◽

Molecular Mechanisms ◽

Apoptotic Cell ◽

Direct Interaction ◽

Anion Channel ◽

Mitochondrial Outer Membrane ◽

Voltage Dependent Anion Channel ◽

Metabolic Intermediate ◽

Voltage Dependent

In tumour cells, elevated levels of mitochondria-bound isoforms of hexokinase (HK-I and HK-II) result in the evasion of apoptosis, thereby allowing the cells to continue proliferating. The molecular mechanisms by which bound HK promotes cell survival are not yet fully understood. Our studies relying on the purified mitochondrial outer membrane protein VDAC (voltage-dependent anion channel), isolated mitochondria or cells in culture suggested that the anti-apoptotic activity of HK-I occurs via modulation of the mitochondrial phase of apoptosis. In the present paper, a direct interaction of HK-I with bilayer-reconstituted purified VDAC, inducing channel closure, is demonstrated for the first time. Moreover, HK-I prevented the Ca2+-dependent opening of the mitochondrial PTP (permeability transition pore) and release of the pro-apoptotic protein cytochrome c. The effects of HK-I on VDAC activity and PTP opening were prevented by the HK reaction product glucose 6-phosphate, a metabolic intermediate in most biosynthetic pathways. Furthermore, glucose 6-phosphate re-opened both the VDAC and the PTP closed by HK-I. The HK-I-mediated effects on VDAC and PTP were not observed using either yeast HK or HK-I lacking the N-terminal hydrophobic peptide responsible for binding to mitochondria, or in the presence of an antibody specific for the N-terminus of HK-I. Finally, HK-I overexpression in leukaemia-derived U-937 or vascular smooth muscle cells protected against staurosporine-induced apoptosis, with a decrease of up to 70% in cell death. These results offer insight into the mechanisms by which bound HK promotes tumour cell survival, and suggests that its overexpression not only ensures supplies of energy and phosphometabolites, but also reflects an anti-apoptotic defence mechanism.

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The voltage-dependent anion channel-1 modulates apoptotic cell death

Cell Death and Differentiation ◽

10.1038/sj.cdd.4401599 ◽

2005 ◽

Vol 12 (7) ◽

pp. 751-760 ◽

Cited By ~ 204

Author(s):

H Zaid ◽

S Abu-Hamad ◽

A Israelson ◽

I Nathan ◽

V Shoshan-Barmatz

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Anion Channel ◽

Apoptotic Cell Death ◽

Voltage Dependent Anion Channel ◽

Voltage Dependent

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Voltage-dependent anion channels mediated apoptosis in refractory epilepsy

Open Medicine ◽

10.1515/med-2020-0113 ◽

2020 ◽

Vol 15 (1) ◽

pp. 745-753

Author(s):

Yan Zhao ◽

Wen-Jing Jiang ◽

Lin Ma ◽

Yan Lin ◽

Xing-Bang Wang

Keyword(s):

Cell Death ◽

Essential Role ◽

Refractory Epilepsy ◽

Apoptotic Cell ◽

Anion Channel ◽

Anion Channels ◽

Voltage Dependent Anion Channel ◽

Caspase 9 ◽

Voltage Dependent

AbstractThe purpose of this study was to investigate the role of voltage-dependent anion channel (VDAC) in mitochondria-mediated apoptosis of neurons in refractory epilepsy. Western blot analyses were carried out to detect the changes in cytochrome C, caspase 9, Bax, and Bcl-2. TUNEL assays were also carried out to investigate cell apoptosis under the upregulation and downregulation of VDAC1 with or without Bax or Bcl-2. VDAC1 induced Bax, Bcl-2, and caspase 9, increasing the release of cytochrome C. VDAC1 played an essential role in the apoptotic cell death of refractory epilepsy. It is concluded that VDAC1 plays an important role in refractory epilepsy and could be a possible therapeutic target of anti-epileptic drugs. The current study provides a new understanding of the possible mechanisms of refractory epilepsy.

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Fluoxetine (Prozac) interaction with the mitochondrial voltage-dependent anion channel and protection against apoptotic cell death

FEBS Letters ◽

10.1016/j.febslet.2005.08.020 ◽

2005 ◽

Vol 579 (22) ◽

pp. 5105-5110 ◽

Cited By ~ 60

Author(s):

Edna Nahon ◽

Adrian Israelson ◽

Salah Abu-Hamad ◽

Varda Shoshan-Barmatz

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Anion Channel ◽

Apoptotic Cell Death ◽

Voltage Dependent Anion Channel ◽

Voltage Dependent

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Hexokinase-I Protection against Apoptotic Cell Death Is Mediated via Interaction with the Voltage-dependent Anion Channel-1

Journal of Biological Chemistry ◽

10.1074/jbc.m708216200 ◽

2008 ◽

Vol 283 (19) ◽

pp. 13482-13490 ◽

Cited By ~ 157

Author(s):

Salah Abu-Hamad ◽

Hilal Zaid ◽

Adrian Israelson ◽

Edna Nahon ◽

Varda Shoshan-Barmatz

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Anion Channel ◽

Apoptotic Cell Death ◽

Voltage Dependent Anion Channel ◽

Voltage Dependent

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

Scientific Reports ◽

10.1038/s41598-020-79056-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Hadar Klapper-Goldstein ◽

Ankit Verma ◽

Sigal Elyagon ◽

Roni Gillis ◽

Michael Murninkas ◽

...

Keyword(s):

Myocardial Infarction ◽

Apoptotic Cell ◽

Anion Channel ◽

Immunohistochemical Analysis ◽

Voltage Dependent Anion Channel ◽

Cardiac Tissues ◽

Therapeutic Implications ◽

Voltage Dependent ◽

Models Of Lupus

AbstractThe 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. In the present study, we explored the expression of VDAC1 in the diseased myocardium of humans and rats. In addition, we evaluated the effect of VBIT-4 treatment on the atrial structural and electrical remodeling of rats exposed to excessive aldosterone levels. Immunohistochemical analysis of commercially available human cardiac tissues revealed marked overexpression of VDAC1 in post-myocardial infarction patients, as well as in patients with chronic ventricular dilatation\dysfunction. In agreement, rats exposed to myocardial infarction or to excessive aldosterone had a marked increase of VDAC1 in both ventricular and atrial tissues. Immunofluorescence staining indicated a punctuated appearance typical for mitochondrial-localized VDAC1. Finally, VBIT-4 treatment attenuated the atrial fibrotic load of rats exposed to excessive aldosterone without a notable effect on the susceptibility to atrial fibrillation episodes induced by burst pacing. Our results indicate that VDAC1 overexpression is associated with myocardial abnormalities in common pathological settings. Our data also indicate that inhibition of the VDAC1 can reduce excessive fibrosis in the atrial myocardium, a finding which may have important therapeutic implications. The exact mechanism\s of this beneficial effect need further studies.

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Biochemical and Genetic Analysis of the Mitochondrial Response of Yeast to BAX and BCL-XL

Molecular and Cellular Biology ◽

10.1128/mcb.20.9.3125-3136.2000 ◽

2000 ◽

Vol 20 (9) ◽

pp. 3125-3136 ◽

Cited By ~ 114

Author(s):

Atan Gross ◽

Kirsten Pilcher ◽

Elizabeth Blachly-Dyson ◽

Emy Basso ◽

Jennifer Jockel ◽

...

Keyword(s):

Cell Death ◽

Mitochondrial Genome ◽

Atp Synthase ◽

Mitochondrial Permeability Transition ◽

Family Members ◽

Growth Arrest ◽

Anion Channel ◽

Cell Killing ◽

Β Subunit ◽

Voltage Dependent Anion Channel

ABSTRACT The BCL-2 family includes both proapoptotic (e.g., BAX and BAK) and antiapoptotic (e.g., BCL-2 and BCL-XL) molecules. The cell death-regulating activity of BCL-2 members appears to depend on their ability to modulate mitochondrial function, which may include regulation of the mitochondrial permeability transition pore (PTP). We examined the function of BAX and BCL-XL using genetic and biochemical approaches in budding yeast because studies with yeast suggest that BCL-2 family members act upon highly conserved mitochondrial components. In this study we found that in wild-type yeast, BAX induced hyperpolarization of mitochondria, production of reactive oxygen species, growth arrest, and cell death; however, cytochrome c was not released detectably despite the induction of mitochondrial dysfunction. Coexpression of BCL-XL prevented all BAX-mediated responses. We also assessed the function of BCL-XL and BAX in the same strain of Saccharomyces cerevisiae with deletions of selected mitochondrial proteins that have been implicated in the function of BCL-2 family members. BAX-induced growth arrest was independent of the tested mitochondrial components, including voltage-dependent anion channel (VDAC), the catalytic β subunit or the δ subunit of the F0F1-ATP synthase, mitochondrial cyclophilin, cytochrome c, and proteins encoded by the mitochondrial genome as revealed by [rho 0] cells. In contrast, actual cell killing was dependent upon select mitochondrial components including the β subunit of ATP synthase and mitochondrial genome-encoded proteins but not VDAC. The BCL-XL protection from either BAX-induced growth arrest or cell killing proved to be independent of mitochondrial components. Thus, BAX induces two cellular processes in yeast which can each be abrogated by BCL-XL: cell arrest, which does not require aspects of mitochondrial biochemistry, and cell killing, which does.

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