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Cited by 408Cell death mechanisms and regulationMitochondrial Function and PathologyCancer, Hypoxia, and Metabolism

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

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AZOULAY-ZOHAR, Heftsi, ISRAELSON, Adrian, ABU-HAMAD, Salah, SHOSHAN-BARMATZ, Varda·2004·Biochemical Journal
DOI 10.1042/bj20031465PMC PMC1223882
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Abstract

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 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.

    “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 [105]

    The ‘HK-I interacts specifically with VDAC’ section (page unavailable) shows that HK-I interacts with the cytosolic face of VDAC, but identifies the N-terminal binding region as belonging to HK-I, not VDAC1. The ‘Expression of HK-I in cell culture’ section (page unavailable) reports protection against staurosporine-induced apoptosis in cultured cells. The paper does not establish binding to the N-terminus of VDAC1 or protection in an in vivo system. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Hexokinases I and II can translocate to the mitochondrial outer membrane, where their catalytic activities are less sensitive to product inhibition.

    “hexokinases I and II can translocate to the mitochondrial outer membrane where their catalytic activities are less sensitive to product inhibition (Azoulay-Zohar et al., 2004; Hashimoto and Wilson, 2002; John et al., 2011).”

    From Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle (2012) · cites this paper as Azoulay-Zohar et al., 2004

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Authors
AZOULAY-ZOHAR, H., ISRAELSON, A., ABU-HAMAD, S., & SHOSHAN-BARMATZ, V.
Affiliations
  • Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
  • Ben-Gurion University of the Negev (IL)
ORCID
ISRAELSON, Adrian
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2004-01-15
Volume
377
Issue
2
Pages
347-355
ISSN
  • 0264-6021 (ISSN-L)
  • 1470-8728
DOI
10.1042/bj20031465
PMC
PMC1223882
OpenAlex
W2100262552
Cited by
408
References
52
Citations by year
2026: 9 · 2025: 8 · 2024: 12 · 2023: 16 · 2022: 20 · 2021: 17 · 2020: 14 · 2019: 12 · 2018: 23 · 2017: 24 · 2016: 21 · 2015: 13 · 2014: 29 · 2013: 19 · 2012: 18
FWCI
8.41
Type
journal article
Language
en
Open access
Locations
  • Biochemical Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • 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, voltage-dependent anion channel, mitochondrial permeability transition pore, cytochrome c release, apoptosis evasion, glucose-6-phosphate, mitochondrial outer membrane, tumor cell survival, staurosporine-induced apoptosis, U937 cells, vascular smooth muscle cells
MeSH terms
Mitochondrial Permeability Transition Pore, Animals, Cell Line, Hexokinase, Humans, Ion Channels, Mitochondria, Apoptosis, Porins, Patch-Clamp Techniques, Glucose-6-Phosphate, Staurosporine, U937 Cells, Mitochondrial Membrane Transport Proteins, Cytochromes c, Voltage-Dependent Anion Channels, Rats

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