Regulation and cytoprotective role of hexokinase III

Eugene Wyatt, Rongxue Wu, Wael Rabeh, Hee Won Park, Mohsen Ghanefar, Hossein Ardehali

Research output: Contribution to journalArticle

Abstract

Background: Hexokinases (HKs) catalyze the first step in glucose metabolism. Of the three mammalian 100-kDa HK isoforms, HKI and II can bind to mitochondria and protect against cell death. HKIII does not bind mitochondria, and little is known about its regulation or cytoprotective effects. We studied the regulation of HKIII at the transcriptional and protein levels and investigated its role in cellular protection. Methodology/Principal Findings: We show that like HKII, HKIII expression is regulated by hypoxia, but other factors that regulate HKII expression have no effect on HKIII levels. This transcriptional regulation is partially dependent on hypoxiainducible factor (HIF) signaling. We also demonstrate regulation at the protein level, as mutations in putative N-terminal substrate binding residues altered C-terminal catalytic activity, suggesting that HKIII activity is governed, in part, by interactions between these two domains. Overexpression of HKIII reduced oxidant-induced cell death, increased ATP levels, decreased the production of reactive oxygen species (ROS), and preserved mitochondrial membrane potential. HKIII overexpression was also associated with higher levels of transcription factors that regulate mitochondrial biogenesis, and greater total mitochondrial DNA content. Attempts to target HKIII to the mitochondria by replacing its N-terminal 32-aminoacid sequence with the mitochondrial-targeting sequence of HKII led to protein aggregation, suggesting that this region is necessary to maintain proper protein folding and solubility. Conclusions/Significance: These results suggest that HKIII is regulated by hypoxia and there are functional interactions between its two halves. Furthermore, HKIII exerts protective effects against oxidative stress, perhaps by increasing ATP levels, reducing oxidant-induced ROS production, preserving mitochondrial membrane potential, and increasing mitochondrial biogenesis.

Original languageEnglish (US)
Article numbere13823
JournalPLoS One
Volume5
Issue number11
DOIs
StatePublished - Nov 19 2010

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Mitochondria
Hexokinase
hexokinase
mitochondria
Mitochondrial Membrane Potential
Organelle Biogenesis
Cell death
membrane potential
Oxidants
oxidants
cell death
hypoxia
reactive oxygen species
Reactive Oxygen Species
Cell Death
Adenosine Triphosphate
Membranes
Protein folding
Proteins
Oxidative stress

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Wyatt, E., Wu, R., Rabeh, W., Park, H. W., Ghanefar, M., & Ardehali, H. (2010). Regulation and cytoprotective role of hexokinase III. PLoS One, 5(11), [e13823]. https://doi.org/10.1371/journal.pone.0013823

Regulation and cytoprotective role of hexokinase III. / Wyatt, Eugene; Wu, Rongxue; Rabeh, Wael; Park, Hee Won; Ghanefar, Mohsen; Ardehali, Hossein.

In: PLoS One, Vol. 5, No. 11, e13823, 19.11.2010.

Research output: Contribution to journalArticle

Wyatt, E, Wu, R, Rabeh, W, Park, HW, Ghanefar, M & Ardehali, H 2010, 'Regulation and cytoprotective role of hexokinase III', PLoS One, vol. 5, no. 11, e13823. https://doi.org/10.1371/journal.pone.0013823
Wyatt E, Wu R, Rabeh W, Park HW, Ghanefar M, Ardehali H. Regulation and cytoprotective role of hexokinase III. PLoS One. 2010 Nov 19;5(11). e13823. https://doi.org/10.1371/journal.pone.0013823
Wyatt, Eugene ; Wu, Rongxue ; Rabeh, Wael ; Park, Hee Won ; Ghanefar, Mohsen ; Ardehali, Hossein. / Regulation and cytoprotective role of hexokinase III. In: PLoS One. 2010 ; Vol. 5, No. 11.
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