DJ1 represses glycolysis and cell proliferation by transcriptionally up-regulatingpink1

Abstract

DJ1 is a multifunctional protein whose mutations cause autosomal recessive early-onset Parkinson disease (PD). DJ1 loss of function disrupts mitochondrial function, but the signaling pathway whereby it interferes with energy metabolism is unknown. Here, we found that mouse embryonic fibroblasts obtained from DJ1-null (dj1-/-) mice showed higher glycolytic rate than those from wild type DJ1 (dj1+/+). This effect could be counteracted by the expression of the full-length cDNA encoding the wild type DJ1, but not its DJ1-L166P mutant form associated with PD. Loss of DJ1 increased hypoxiainducible factor-1α (Hif1α) protein abundance and cell proliferation. To understand the molecular mechanism responsible for these effects, we focused on 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, Lopez-Fabuel, Fernandez, Martins, Almeida and Bolaños, 2014, Nature Communications 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 transcription factor, directly interacted with pink1 promoter stimulating its transcriptional activity. These results indicate that DJ1 regulates cell metabolism and proliferation through Pink1.

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

“…This suggests that DJ-1 may interact with PINK1, parkin, or FBXO7 in inducing mitophagy in a yet-to-be elucidated mechanism. Recent data demonstrates that DJ-1 binds to Foxo3a transcription factor, which then binds to the promoter of PINK1, resulting in an upregulation of PINK1 transcription (Requejo-Aguilar et al, 2015). Whether this transcriptional regulation provides a protective role in upregulating mitophagy machinery is unclear.…”

Mitochondrial control of cell bioenergetics in Parkinson’s disease

“…Nuclear translocation of DJ-1 occurs by oxidation of the Cys 106 that acts as a redox sensor [259, 262]. Neurons and MEF defective in DJ-1 show decreased complex I activity and mitochondrial respiration [88, 263], along with increased oxidative stress accompanied by enhanced glycolysis [33]. MEF knockout for DJ1 show decreased Δψ m and increased mitochondrial permeability transition pore [264].…”

“…Interestingly, decreased DJ-1 expression is observed in PD patients and in patients suffering from T2DM, indicating the interrelation between these diseases [41]. In addition, DJ-1 has been shown to transcriptionally co-activate PINK1 expression by binding to FOXOa3; accordingly, DJ-1 loss causes decreased complex I activity and increased glycolysis via regulating PINK1 [33]. Similar effects on glucose metabolism take place in DJ-1 knockout mouse skeletal muscle, where a higher energy expenditure, AMPK activation, and uncoupled mitochondrial respiration has been observed leading to a Warburg-like metabolic reprogramming [273].…”

“…DJ-1is also involved in the degradation of misfolded proteins, thus protecting from mitochondrial fragmentation after damage; it has been observed that Parkin, Pink1 and DJ-1 form a complex having E3 ligase activity [32]. However, many reports have shown that DJ-1 acts in parallel to, or up-stream of, the Pink1/Parkin pathway [33, 34]. DJ-1, via its Cys 106 , may also act as a redox sensor protein exerting protection against oxidative stress [35].…”

Genes involved in the development of Parkinson

“…RequejoAguilar et al associated the DJ-1 gene to cell metabolism and proliferation regulation through PINK1 [118]. In fact, this gene is pointed out as a positive regulator of PINK1 gene transcription [118].…”