Mitochondrial hexokinase HKI is a novel substrate of the Parkin ubiquitin ligase.
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.
Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
Kei
K
Okatsu
Shun-Ichiro
S
Iemura
Fumika
F
Koyano
Etsu
E
Go
Mayumi
M
Kimura
Tohru
T
Natsume
Keiji
K
Tanaka
Noriyuki
N
Matsuda
D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000031:analogs & derivatives / Q000494:pharmacology; D002384:Catalysis; D057809:HEK293 Cells; D006367:HeLa Cells; D006593:Hexokinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D050995:Voltage-Dependent Anion Channel 1 / Q000096:biosynthesis / Q000378:metabolism
C525595:CISD1 protein, human; D024101:Mitochondrial Proteins; C494762:VDAC1 protein, human; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D050995:Voltage-Dependent Anion Channel 1; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C472074:HK1 protein, human; D006593:Hexokinase; D046988:Proteasome Endopeptidase Complex