Mitochondrial hexokinase HKI is a novel substrate of the Parkin ubiquitin ligase.

Abstract

Dysfunction of Parkin, a RING-IBR-RING motif containing protein, causes autosomal recessive familial Parkinsonism. Biochemically, Parkin is a ubiquitin-ligating enzyme (E3) that catalyzes ubiquitin transfer from ubiquitin-activating and -conjugating enzymes (E1/E2) to a substrate. Recent studies have revealed that Parkin localizes in the cytoplasm and its E3 activity is repressed under steady-state conditions. In contrast, Parkin moves to mitochondria with low membrane potential, thereby activating the latent enzymatic activity of the protein, which in turn triggers Parkin-mediated ubiquitylation of numerous mitochondrial substrates. However, the mechanism of how Parkin-catalyzed ubiquitylation maintains mitochondrial integrity has yet to be determined. To begin to address this, we screened for novel Parkin substrate(s) and identified mitochondrial hexokinase I (HKI) as a candidate. Following a decrease in membrane potential, Parkin ubiquitylation of HKI leads to its proteasomal degradation. Moreover, most disease-relevant mutations of Parkin hinder this event and endogenous HKI is ubiquitylated upon dissipation of mitochondrial membrane potential in genuine-Parkin expressing cells, suggesting its physiological importance.

• Authors: Kei Okatsu, Shun-Ichiro Iemura, Fumika Koyano, Etsu Go, Mayumi Kimura, Tohru Natsume, Keiji Tanaka, Noriyuki Matsuda
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 428 Issue 1 Pg. 197-202 (Nov 09 2012) ISSN: 1090-2104 [Electronic] United States
• PMID: 23068103 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• CISD1 protein, human
• Mitochondrial Proteins
• VDAC1 protein, human
• Carbonyl Cyanide m-Chlorophenyl Hydrazone
• Voltage-Dependent Anion Channel 1
• Ubiquitin-Protein Ligases
• parkin protein
• HK1 protein, human
• Hexokinase
• Proteasome Endopeptidase Complex

Topics

• Carbonyl Cyanide m-Chlorophenyl Hydrazone (analogs & derivatives, pharmacology)
• Catalysis
• HEK293 Cells
• HeLa Cells
• Hexokinase (biosynthesis, genetics, metabolism)
• Humans
• Mitochondria (enzymology)
• Mitochondrial Proteins (biosynthesis, metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Substrate Specificity
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination
• Voltage-Dependent Anion Channel 1 (biosynthesis, metabolism)