Abstract
DnaJ-1 or hsp40/hdj-1 (DJ1) is a multi-functional protein whose mutations cause autosomal recessive early-onset Parkinson's disease (PD). DJ1 loss of function disrupts mitochondrial function, but the signalling pathway, whereby it interferes with energy metabolism, is unknown. In the present study, we found that mouse embryonic fibroblasts (MEFs) obtained from DJ1-null (dj1-/-) mice showed higher glycolytic rate than those from wild-type (WT) DJ1 (dj1+/+). This effect could be counteracted by the expression of the full-length cDNA encoding the WT DJ1, but not its DJ1-L166P mutant form associated with PD. Loss of DJ1 increased hypoxia-inducible factor-1α (Hif1α) protein abundance and cell proliferation. To understand the molecular mechanism responsible for these effects, we focused on phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-induced protein kinase-1 (Pink1), a PD-associated protein whose loss was recently reported to up-regulate glucose metabolism and to sustain cell proliferation [Requejo-Aguilar et al. (2014) Nat. Commun. 5, 4514]. Noticeably, we found that the alterations in glycolysis, Hif1α and proliferation of DJ1-deficient cells were abrogated by the expression of Pink1. Moreover, we found that loss of DJ1 decreased pink1 mRNA and Pink1 protein levels and that DJ1, by binding with Foxo3a (forkhead box O3a) transcription factor, directly interacted with the pink1 promoter stimulating its transcriptional activity. These results indicate that DJ1 regulates cell metabolism and proliferation through Pink1.
Highlights
DJ1 was initially identified as an oncogene [1] and it has been attributed antioxidant [2, 3], chaperone [4, 5], transcriptional [6, 7] and RNA regulatory [8] properties
We found that the alterations in glycolysis, HIF1α and proliferation of DJ1-deficient cells were abrogated by the expression of protein kinase-1 (Pink1)
We found that loss of DJ1 increased the glycolytic rate and cell proliferation, and that these effects were counteracted by the expression of Pink1
Summary
DJ1 was initially identified as an oncogene [1] and it has been attributed antioxidant [2, 3], chaperone [4, 5], transcriptional [6, 7] and RNA regulatory [8] properties. These results indicate that DJ1 regulates cell metabolism and proliferation through Pink1. We found that loss of DJ1 increased the glycolytic rate and cell proliferation, and that these effects were counteracted by the expression of Pink1.
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