Distinct Mechanisms of Pathogenic DJ-1 Mutations in Mitochondrial Quality Control

The deglycase and chaperone protein DJ-1 is pivotal for cellular oxidative stress responses and mitochondrial quality control. Mutations in PARK7, encoding DJ-1, are associated with early-onset familial Parkinson’s disease and lead to pathological oxidative stress and/or disrupted protein degradation by the proteasome. The aim of this study was to gain insights into the pathogenic mechanisms of selected DJ-1 missense mutations, by characterizing protein–protein interactions, core parameters of mitochondrial function, quality control regulation via autophagy, and cellular death following dopamine accumulation. We report that the DJ-1M26I mutant influences DJ-1 interactions with SUMO-1, in turn enhancing removal of mitochondria and conferring increased cellular susceptibility to dopamine toxicity. By contrast, the DJ-1D149A mutant does not influence mitophagy, but instead impairs Ca2+ dynamics and free radical homeostasis by disrupting DJ-1 interactions with a mitochondrial accessory protein known as DJ-1-binding protein (DJBP/EFCAB6). Thus, individual DJ-1 mutations have different effects on mitochondrial function and quality control, implying mutation-specific pathomechanisms converging on impaired mitochondrial homeostasis

Biomechanical Determinants of the Reactive Strength Index During Drop Jumps

The Reactive Strength Index (RSI) is often used to quantify drop-jump (DJ) performance; however, not much is known about its biomechanical determinants. The purpose of this study was to investigate the correlations between the RSI and several biomechanical variables calculated from DJ performed with different initial drop heights. Twelve male NCAA Division I basketball players performed DJs from drop heights of 30, 45, and 60 cm. Force plates were used to calculate DJ performance parameters (ie, DJ height, contact time, and RSI) and DJ biomechanical variables (ie, vertical stiffness and eccentric/concentric energetics). Regression analyses were used to assess the correlations between variables at each drop height, and ANOVAs were used to assess the differences of all variables across drop heights. Follow-up analyses used 2 neural networks to determine if DJ performance and biomechanical data could accurately classify DJ trials by drop-height condition. Vertical-stiffness values were significantly correlated with RSI at each height but did not change across drop heights. Surprisingly, the RSI and other DJ parameters also did not vary across drop height, which resulted in the inability of these variables to accurately classify DJ trials. Given that vertical stiffness did not change across drop height and was highly correlated with RSI at each height, the RSI appears to reflect biomechanical behavior related to vertical stiffness during DJ. However, the inability of the RSI to accurately classify drop-height condition questions the use of RSI profiles established from DJs from different heights

The Interplay among PINK1/PARKIN/Dj-1 Network during Mitochondrial Quality Control in Cancer Biology: Protein Interaction Analysis

PARKIN (E3 ubiquitin ligase PARK2), PINK1 (PTEN induced kinase 1) and DJ-1 (PARK7) are proteins involved in autosomal recessive parkinsonism, and carcinogenic processes. In damaged mitochondria, PINK1's importing into the inner mitochondrial membrane is prevented, PARKIN presents a partial mitochondrial localization at the outer mitochondrial membrane and DJ-1 relocates to mitochondria when oxidative stress increases. Depletion of these proteins result in abnormal mitochondrial morphology. PINK1, PARKIN, and DJ-1 participate in mitochondrial remodeling and actively regulate mitochondrial quality control. In this review, we highlight that PARKIN, PINK1, and DJ-1 should be regarded as having an important role in Cancer Biology. The STRING database and Gene Ontology (GO) enrichment analysis were performed to consolidate knowledge of well-known protein interactions for PINK1, PARKIN, and DJ-1 and envisage new ones. The enrichment analysis of KEGG pathways showed that the PINK1/PARKIN/DJ-1 network resulted in Parkinson disease as the main feature, while the protein DJ-1 showed enrichment in prostate cancer and p53 signaling pathway. Some predicted transcription factors regulating PINK1, PARK2 (PARKIN) and PARK7 (DJ-1) gene expression are related to cell cycle control. We can therefore suggest that the interplay among PINK1/PARKIN/DJ-1 network during mitochondrial quality control in cancer biology may occur at the transcriptional level. Further analysis, like a systems biology approach, will be helpful in the understanding of PINK1/PARKIN/DJ-1 network.Peer reviewedFinal Published versio

DJ-1 interacts with and regulates paraoxonase-2, an enzyme critical for neuronal survival in response to oxidative stress.

Loss-of-function mutations in DJ-1 (PARK7) gene account for about 1% of all familial Parkinson's disease (PD). While its physiological function(s) are not completely clear, DJ-1 protects neurons against oxidative stress in both in vitro and in vivo models of PD. The molecular mechanism(s) through which DJ-1 alleviates oxidative stress-mediated damage remains elusive. In this study, we identified Paraoxonase-2 (PON2) as an interacting target of DJ-1. PON2 activity is elevated in response to oxidative stress and DJ-1 is crucial for this response. Importantly, we showed that PON2 deficiency hypersensitizes neurons to oxidative stress induced by MPP+ (1-methyl-4-phenylpyridinium). Conversely, over-expression of PON2 protects neurons in this death paradigm. Interestingly, PON2 effectively rescues DJ-1 deficiency-mediated hypersensitivity to oxidative stress. Taken together, our data suggest a model by which DJ-1 exerts its antioxidant activities, at least partly through regulation of PON2

Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis

Neoplastic accumulation of mast cells in systemic mastocytosis (SM) associates with activating mutations in the receptor tyrosine kinase KIT. Constitutive activation of tyrosine kinase oncogenes has been linked to imbalances in oxidant/antioxidant mechanisms in other myeloproliferative disorders. However, the impact of KIT mutations on the redox status in SM and the potential therapeutic implications are not well understood. Here, we examined the regulation of reactive oxygen species (ROS) and of the antioxidant protein DJ-1 (PARK-7), which increases with cancer progression and acts to lessen oxidative damage to malignant cells, in relationship with SM severity. ROS levels were increased in both indolent (ISM) and aggressive variants of the disease (ASM). However, while DJ-1 levels were reduced in ISM with lower mast cell burden, they rose in ISM with higher mast cell burden and were significantly elevated in patients with ASM. Studies on mast cell lines revealed that activating KIT mutations induced constant ROS production and consequent DJ-1 oxidation and degradation that could explain the reduced levels of DJ-1 in the ISM population, while IL-6, a cytokine that increases with disease severity, caused a counteracting transcriptional induction of DJ-1 which would protect malignant mast cells from oxidative damage. A mouse model of mastocytosis recapitulated the biphasic changes in DJ-1 and the escalating IL-6, ROS and DJ-1 levels as mast cells accumulate, findings which were reversed with anti-IL-6 receptor blocking antibody. Our findings provide evidence of increased ROS and a biphasic regulation of the antioxidant DJ-1 in variants of SM and implicate IL-6 in DJ-1 induction and expansion of mast cells with KIT mutations. We propose consideration of IL-6 blockade as a potential adjunctive therapy in the treatment of patients with advanced mastocytosis, as it would reduce DJ-1 levels making mutation-positive mast cells vulnerable to oxidative damage

The role of DJ-1 in enhancing mitochondrial quality control

Thesis (M.A.)--Boston UniversityDJ-1 is a cytosolic sensor for oxidative damage which acts on the Mitochondria. It works to curb the negative effects of high membrane potential in mitochondria, but the mechanism of action is still uncertain. This study measured DJ-1’s potential in enchancing mitochondrial quality control in the context of pancreatic B-cells treated with a palmitate and glucose media to promote glucolipotoxicity (GLT). DJ-1 was proven capable of reversing GLT induced changed in mitochondrial morphology in the arenas of Feret’s diameter, aspect ratio, and form factor. We also showed that the mitochondrial membrane potential did not vary with the presence or absence of DJ-1. In addition, DJ-1 was shown capable of limiting the upward boundary of GLT induced increase in mitochondrial membrane potential. Furthermore, an experiment using INS1 cells with GFP-LC3 showed that DJ-1 can decrease the average number of autophagosomes in the cell

DJ-1 as a deglycating enzyme: A unique function to explain a multifaceted protein?

The recently reported deglycating activity of DJ-1 reconciles several features previously described for the protein. The deglycating activity reported for DJ-1 may explain its different subcellular localizations, indeed the protein has been found in the cytoplasm, nucleus, and mitochondria. Moreover, this proposed activity could help to understand the involvement of the protein in Parkinson's disease (PD), tumor growth and diabetes

The Choice of Codes Used by Two Announcers of Dj Fm and Ss Fm Radio Stations in Their Advertisements

This thesis is a study of the choice of codes used by the announcers of DJ FM and SS FM radios in their advertisements, consisting of twenty advertisements from both radios. I applied some theories of codes from Wardaugh (2006), Stockwell (2002), and Holmes (2001) as my main theories. Also, I used the theory of Age and Linguistic choice from Coulmas (2005), and Marketing and Language Choice from Victor (2007) as my supporting theories. The subjects are two announcers of DJ FM and SS FM radios which are in the phase of young adulthood. Furthermore, I found that the announcers from both radio stations used Standard Indonesia as their main code. The conclusion is the target audience of DJ FM and SS FM did not influence the way the announcers chose their codes

Rethinking live electronic music: a DJ perspective

The author critiques the conventional understanding of live electronic music through empirical research on his own DJ practice and investigates others working in the field. In reviewing the opinions of theorists and practitioners in both the live electronic music genre and DJ-ing he argues against the body/machine dialectic that has determined much of the thinking in the former. The author forms a notion of the DJ as a real-time composer working beyond traditional binary distinctions who brings the human body and machine into a mutual relationship. Through practice-led research he charts an investigation beginning in physical human gesture and culminating in digital machine repetition. He concludes that mechanical and digital repetition do not obscure human agency in the production of live works and that this concern is imaginary