Hexokinase activity is required for recruitment of parkin to depolarized mitochondria

Hum Mol Genet. 2014 Jan 1;23(1):145-56. doi: 10.1093/hmg/ddt407. Epub 2013 Aug 19.

Abstract

Autosomal recessive parkinsonism genes contribute to maintenance of mitochondrial function. Two of these, PINK1 and parkin, act in a pathway promoting autophagic removal of depolarized mitochondria. Although recruitment of parkin to mitochondria is PINK1-dependent, additional components necessary for signaling are unclear. We performed a screen for endogenous modifiers of parkin recruitment to depolarized mitochondria and identified hexokinase 2 (HK2) as a novel modifier of depolarization-induced parkin recruitment. Hexose kinase activity was required for parkin relocalization, suggesting the effects are shared among hexokinases including the brain-expressed hexokinase 1 (HK1). Knockdown of both HK1 and HK2 led to a stronger block in parkin relocalization than either isoform alone, and expression of HK2 in primary neurons promoted YFP-parkin recruitment to depolarized mitochondria. Mitochondrial parkin recruitment was attenuated with AKT inhibition, which is known to modulate HK2 activity and mitochondrial localization. We, therefore, propose that Akt-dependent recruitment of hexokinases is a required step in the recruitment of parkin prior to mitophagy.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Gene Knockdown Techniques
  • HeLa Cells
  • Hexokinase / genetics
  • Hexokinase / metabolism*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / physiology*
  • Mitophagy
  • Neurons / metabolism*
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • HK1 protein, human
  • Hexokinase
  • PTEN-induced putative kinase
  • Proto-Oncogene Proteins c-akt