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Glucose phosphorylation and mitochondrial binding are required for the protective effects of hexokinases I and II

Lin Sun1, Shetha Shukair, Tejaswitha Jairaj Naik

  • 1Feinberg Cardiovascular Institute, Northwestern University School of Medicine, Chicago, Illinois, USA.

Molecular and Cellular Biology
|November 28, 2007
PubMed

Insights

Hexokinase (HK) enzymes protect cells from death by both phosphorylating glucose and binding to mitochondria. This dual function, involving glucose metabolism and mitochondrial interactions, is crucial for cellular protection.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Metabolic Disorders

Background:

  • Glucose metabolism is altered in various diseases, including heart disease and cancer.
  • Hexokinase (HK) enzymes initiate glucose metabolism and can bind to mitochondria, offering cellular protection.
  • Overexpression of HKI and HKII has shown protective effects against cell death in tissue culture.

Purpose of the Study:

  • To determine the specific contributions of glucose phosphorylation and mitochondrial binding of HKs to their protective functions.
  • To investigate the role of HKs in cellular protection against oxidative stress.
  • To explore the involvement of VDAC phosphorylation and PKCepsilon in HK-mediated protection.

Main Methods:

  • Expression of full-length, truncated (lacking mitochondrial binding domains), and catalytically inactive HKI and HKII proteins in tissue culture.
  • Assessment of cell death, reactive oxygen species levels, and mitochondrial permeability transition.
  • Experiments conducted on primary neonatal rat cardiomyocytes.
  • Analysis of voltage-dependent anion channel (VDAC) phosphorylation via a protein kinase Cepsilon (PKCepsilon)-dependent pathway.

Main Results:

  • Overexpression of full-length HKI and HKII conferred protection against cell death and reduced reactive oxygen species.
  • Truncated and catalytically inactive HK proteins showed only partial protective effects.
  • HK proteins increased VDAC phosphorylation through a PKCepsilon-dependent pathway.
  • Protective effects were observed in both cell culture and primary cardiomyocytes.

Conclusions:

  • Both glucose phosphorylation and mitochondrial binding activities of HKI and HKII contribute to their protective effects.
  • The protective mechanisms may involve the phosphorylation of VDAC by PKCepsilon.
  • HKs play a significant role in cellular defense against stress through integrated metabolic and mitochondrial functions.

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