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Biochem Biophys Res Commun. 2012 Nov 9;428(1):197-202. doi: 10.1016/j.bbrc.2012.10.041. Epub 2012 Oct 13.

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

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1
Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.

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.

PMID:
23068103
DOI:
10.1016/j.bbrc.2012.10.041
[Indexed for MEDLINE]
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