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Hexokinase-I Protection against Apoptotic Cell Death Is Mediated via Interaction with the Voltage-dependent Anion Channel-1
Open accessAbstract
In brain and tumor cells, the hexokinase isoforms HK-I and HK-II bind to the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane. We have previously shown that HK-I decreases murine VDAC1 (mVDAC1) channel conductance, inhibits cytochrome c release, and protects against apoptotic cell death. Now, we define mVDAC1 residues, found in two cytoplasmic domains, involved in the interaction with HK-I. Protection against cell death by HK-I, as induced by overexpression of native or mutated mVDAC1, served to identify the mVDAC1 amino acids required for interaction with HK-I. HK-I binding to mVDAC1 either in isolated mitochondria or reconstituted in a bilayer was inhibited upon mutation of specific VDAC1 residues. HK-I anti-apoptotic activity was also diminished upon mutation of these amino acids. HK-I-mediated inhibition of cytochrome c release induced by staurosporine was also diminished in cells expressing VDAC1 mutants. Our results thus offer new insights into the mechanism by which HK-I promotes tumor cell survival via inhibition of cytochrome c release through HK-I binding to VDAC1. These results, moreover, point to VDAC1 as a key player in mitochondrially mediated apoptosis and implicate an HK-I-VDAC1 interaction in the regulation of apoptosis. Finally, these findings suggest that interference with the binding of HK-I to mitochondria by VDAC1-derived peptides may offer a novel strategy by which to potentiate the efficacy of conventional chemotherapeutic agents.
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“The hexokinase isoform HK-I binds to the N-terminus of VDAC1 on the cytoplasmic side of the outer mitochondrial membrane and has been shown in both in vitro and in vivo systems to protect against apoptosis [105,106].”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [106]
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Metadata
- Authors
- Abu-Hamad, S., Zaid, H., Israelson, A., Nahon, E., & Shoshan-Barmatz, V.
- Affiliations
- Hospital for Sick Children (CA)
- University of California San Diego (US)
- Ben-Gurion University of the Negev (IL)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 283
- Issue
- 19
- Pages
- 13482-13490
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2054645758
- Cited by
- 278
- References
- 49
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 12 · 2023: 16 · 2022: 15 · 2021: 16 · 2020: 17 · 2019: 13 · 2018: 14 · 2017: 14 · 2016: 9 · 2015: 6 · 2014: 18 · 2013: 16 · 2012: 16
- FWCI
- 8.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- hexokinase 1, VDAC1, apoptosis, cytochrome c release, mitochondrial permeability transition, tumor cell survival, staurosporine, mitochondrial outer membrane
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Cell Line, Cytosol, Gene Expression Regulation, Hexokinase, Humans, Molecular Sequence Data, Mutation, Protein Binding, Sequence Alignment, Conserved Sequence, Apoptosis, Cytochromes c, Protein Kinase Inhibitors, Voltage-Dependent Anion Channel 1, Mice
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