Increased H2O2 levels and p53 stabilization lead to mitochondrial dysfunction in XPC-deficient cells

2021 ◽  
Author(s):  
T S Freire ◽  
M P Mori ◽  
J N F A Miranda ◽  
L Y M Muta ◽  
F T Machado ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Cellular Response ◽  
Critical Role ◽  
Critical Factor ◽  
Complementation Group ◽  
Complex Iii ◽  
H2o2 Production ◽  
Isogenic Line ◽  
Mitochondrial Stress ◽  
P53 Expression

Abstract XPC deficiency is associated with mitochondrial dysfunction, increased mitochondrial H2O2 production and sensitivity to the Complex III inhibitor antimycin A (AA), through a yet unclear mechanism. We found an imbalanced expression of several proteins that participate in important mitochondrial function and increased expression and phosphorylation of the tumor suppressor p53 in Xeroderma pigmentosum complementation group C (XP-C) (XPC-null) cells compared with an isogenic line corrected in locus with wild-type XPC (XPC-wt). Interestingly, inhibition of p53 nuclear import reversed the overexpression of mitochondrial proteins, whereas AA treatment increased p53 expression more strongly in the XP-C cells. However, inhibition of p53 substantially increased XP-C cellular sensitivity to AA treatment, suggesting that p53 is a critical factor mediating the cellular response to mitochondrial stress. On the other hand, treatment with the antioxidant N-acetylcysteine increased glutathione concentration and decreased basal H2O2 production, p53 levels and sensitivity to AA treatment in the XPC-null back to the levels found in XPC-wt cells. Thus, the results suggest a critical role for mitochondrially generated H2O2 in the regulation of p53 expression, which in turn modulates XP-C sensitivity to agents that cause mitochondrial stress.

scholarly journals Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

2016 ◽  
Vol 113 (16) ◽  
pp. E2231-E2240 ◽  
Author(s):  
Danny Bavli ◽  
Sebastian Prill ◽  
Elishai Ezra ◽  
Gahl Levy ◽  
Merav Cohen ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Real Time ◽  
Critical Role ◽  
Mitochondrial Damage ◽  
Mitochondrial Activity ◽  
Prognostic Information ◽  
Mitochondrial Stress ◽  
Cellular Adaptation ◽  
Chip Technology ◽  
On Chip

Microfluidic organ-on-a-chip technology aims to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity, as well as pluripotency and disease processes. However, current methods to evaluate mitochondrial activity still rely on end-point assays, resulting in limited kinetic and prognostic information. Here, we present a liver-on-chip device capable of maintaining human tissue for over a month in vitro under physiological conditions. Mitochondrial respiration was monitored in real time using two-frequency phase modulation of tissue-embedded phosphorescent microprobes. A computer-controlled microfluidic switchboard allowed contiguous electrochemical measurements of glucose and lactate, providing real-time analysis of minute shifts from oxidative phosphorylation to anaerobic glycolysis, an early indication of mitochondrial stress. We quantify the dynamics of cellular adaptation to mitochondrial damage and the resulting redistribution of ATP production during rotenone-induced mitochondrial dysfunction and troglitazone (Rezulin)-induced mitochondrial stress. We show troglitazone shifts metabolic fluxes at concentrations previously regarded as safe, suggesting a mechanism for its observed idiosyncratic effect. Our microfluidic platform reveals the dynamics and strategies of cellular adaptation to mitochondrial damage, a unique advantage of organ-on-chip technology.

scholarly journals Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3

2021 ◽  
Vol 22 (15) ◽  
pp. 8117
Author(s):  
Nunzia D’Onofrio ◽  
Elisa Martino ◽  
Luigi Mele ◽  
Antonino Colloca ◽  
Martina Maione ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Protein Levels

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.

scholarly journals A Genome-Wide Screen in Saccharomyces cerevisiae Reveals a Critical Role for Oxidative Phosphorylation in Cellular Tolerance to Lithium Hexafluorophosphate

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 888
Author(s):  
Xuejiao Jin ◽  
Jie Zhang ◽  
Tingting An ◽  
Huihui Zhao ◽  
Wenhao Fu ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Oxidative Phosphorylation ◽  
Cellular Response ◽  
Critical Role ◽  
Lithium Ion ◽  
Deletion Mutants ◽  
High Concentration ◽  
Genome Wide ◽  
A Genome ◽  
Lithium Hexafluorophosphate

Lithium hexafluorophosphate (LiPF6) is one of the leading electrolytes in lithium-ion batteries, and its usage has increased tremendously in the past few years. Little is known, however, about its potential environmental and biological impacts. In order to improve our understanding of the cytotoxicity of LiPF6 and the specific cellular response mechanisms to it, we performed a genome-wide screen using a yeast (Saccharomyces cerevisiae) deletion mutant collection and identified 75 gene deletion mutants that showed LiPF6 sensitivity. Among these, genes associated with mitochondria showed the most enrichment. We also found that LiPF6 is more toxic to yeast than lithium chloride (LiCl) or sodium hexafluorophosphate (NaPF6). Physiological analysis showed that a high concentration of LiPF6 caused mitochondrial damage, reactive oxygen species (ROS) accumulation, and ATP content changes. Compared with the results of previous genome-wide screening for LiCl-sensitive mutants, we found that oxidative phosphorylation-related mutants were specifically hypersensitive to LiPF6. In these deletion mutants, LiPF6 treatment resulted in higher ROS production and reduced ATP levels, suggesting that oxidative phosphorylation-related genes were important for counteracting LiPF6-induced toxicity. Taken together, our results identified genes specifically involved in LiPF6-modulated toxicity, and demonstrated that oxidative stress and ATP imbalance maybe the driving factors in governing LiPF6-induced toxicity.

scholarly journals Impact of Carcinogenic Chromium on the Cellular Response to Proteotoxic Stress

2019 ◽  
Vol 20 (19) ◽  
pp. 4901 ◽  
Author(s):  
Leonardo M. R. Ferreira ◽  
Teresa Cunha-Oliveira ◽  
Margarida C. Sobral ◽  
Patrícia L. Abreu ◽  
Maria Carmen Alpoim ◽  
...  
Keyword(s):  
Stress Response ◽  
Health Effects ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Chemical Properties ◽  
Adverse Health Effects ◽  
Proteotoxic Stress ◽  
Adverse Health ◽  
The Impact

Worldwide, several million workers are employed in the various chromium (Cr) industries. These workers may suffer from a variety of adverse health effects produced by dusts, mists and fumes containing Cr in the hexavalent oxidation state, Cr(VI). Of major importance, occupational exposure to Cr(VI) compounds has been firmly associated with the development of lung cancer. Counterintuitively, Cr(VI) is mostly unreactive towards most biomolecules, including nucleic acids. However, its intracellular reduction produces several species that react extensively with biomolecules. The diversity and chemical versatility of these species add great complexity to the study of the molecular mechanisms underlying Cr(VI) toxicity and carcinogenicity. As a consequence, these mechanisms are still poorly understood, in spite of intensive research efforts. Here, we discuss the impact of Cr(VI) on the stress response—an intricate cellular system against proteotoxic stress which is increasingly viewed as playing a critical role in carcinogenesis. This discussion is preceded by information regarding applications, chemical properties and adverse health effects of Cr(VI). A summary of our current understanding of cancer initiation, promotion and progression is also provided, followed by a brief description of the stress response and its links to cancer and by an overview of potential molecular mechanisms of Cr(VI) carcinogenicity.

scholarly journals The binding of NCAM to FGFR1 induces a specific cellular response mediated by receptor trafficking

2009 ◽  
Vol 187 (7) ◽  
pp. 1101-1116 ◽  
Author(s):  
Chiara Francavilla ◽  
Paola Cattaneo ◽  
Vladimir Berezin ◽  
Elisabeth Bock ◽  
Diletta Ami ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cellular Response ◽  
Critical Role ◽  
Biological Significance ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Fgf Receptor ◽  
Neural Cell Adhesion ◽  
Sustained Activation

Neural cell adhesion molecule (NCAM) associates with fibroblast growth factor (FGF) receptor-1 (FGFR1). However, the biological significance of this interaction remains largely elusive. In this study, we show that NCAM induces a specific, FGFR1-mediated cellular response that is remarkably different from that elicited by FGF-2. In contrast to FGF-induced degradation of endocytic FGFR1, NCAM promotes the stabilization of the receptor, which is recycled to the cell surface in a Rab11- and Src-dependent manner. In turn, FGFR1 recycling is required for NCAM-induced sustained activation of various effectors. Furthermore, NCAM, but not FGF-2, promotes cell migration, and this response depends on FGFR1 recycling and sustained Src activation. Our results implicate NCAM as a nonconventional ligand for FGFR1 that exerts a peculiar control on the intracellular trafficking of the receptor, resulting in a specific cellular response. Besides introducing a further level of complexity in the regulation of FGFR1 function, our findings highlight the link of FGFR recycling with sustained signaling and cell migration and the critical role of these events in dictating the cellular response evoked by receptor activation.

Juggling on the line

2015 ◽  
Vol 37 (4) ◽  
pp. 459-474 ◽  
Author(s):  
Samantha Evans
Keyword(s):  
Critical Role ◽  
Case Study Research ◽  
Critical Factor ◽  
Employee Relations ◽  
Front Line ◽  
Structured Interviews ◽  
Line Managers ◽  
Content Type ◽  
Nuanced Understanding ◽  
High Level

Purpose – The purpose of this paper is to examine the interplay between the role of front line managers (FLMs) and their contribution to the reported gap between intended and actual human resource management (HRM). Design/methodology/approach – The findings draw on case study research using 51 semi-structured interviews with managers across two UK retail organisations between 2012 and 2013. Findings – This paper argues that FLMs are key agents in people management and play a critical role in the gap between intended and actual employee relations (ER) and HRM. The research found that these managers held a high level of responsibility for people management, but experienced a lack of institutional support, monitoring or incentives to implement according to central policy. This provided an opportunity for them to modify or resist intended policy and the tensions inherent in their role were a critical factor in this manipulation of their people management responsibilities. Research limitations/implications – The data were collected from only one industry and two organisations so the conclusions need to be considered within these limitations. Practical implications – Efforts to address the gap between intended and actual ER/HRM within organisations will need to consider the role tensions of both front line and middle managers. Originality/value – This research provides a more nuanced understanding of the interplay between FLMs and the gap between intended and actual HRM within organisations. It addresses the issue of FLMs receiving less attention in the HRM-line management literature and the call to research their role in the translation of policy into practice.

scholarly journals Diesel Exhaust Particle Exposure Compromises Alveolar Macrophage Mitochondrial Bioenergetics

2019 ◽  
Vol 20 (22) ◽  
pp. 5598
Author(s):  
Jonathan L. Gibbs ◽  
Blake W. Dallon ◽  
Joshua B. Lewis ◽  
Chase M. Walton ◽  
Juan A. Arroyo ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Diesel Exhaust ◽  
Critical Role ◽  
Cell Communication ◽  
Diesel Exhaust Particle ◽  
Diesel Exhaust Particles ◽  
The Body ◽  
Whole Body ◽  
H2o2 Production ◽  
Pulmonary Macrophages

Diesel exhaust particles (DEPs) are known pathogenic pollutants that constitute a significant quantity of air pollution. Given the ubiquitous presence of macrophages throughout the body, including the lungs, as well as their critical role in tissue and organismal metabolic function, we sought to determine the effect of DEP exposure on macrophage mitochondrial function. Following daily DEP exposure in mice, pulmonary macrophages were isolated for mitochondrial analyses, revealing reduced respiration rates and dramatically elevated H2O2 levels. Serum ceramides and inflammatory cytokines were increased. To determine the degree to which the changes in mitochondrial function in macrophages were not dependent on any cross-cell communication, primary pulmonary murine macrophages were used to replicate the DEP exposure in a cell culture model. We observed similar changes as seen in pulmonary macrophages, namely diminished mitochondrial respiration, but increased H2O2 production. Interestingly, when treated with myriocin to inhibit ceramide biosynthesis, these DEP-induced mitochondrial changes were mitigated. Altogether, these data suggest that DEP exposure may compromise macrophage mitochondrial and whole-body function via pathologic alterations in macrophage ceramide metabolism.

scholarly journals PSYCHOGEOGRAPHICAL EXPERIENCE BETWEEN THE SELF AND THE PLACE

2022 ◽  
Vol 7 (1) ◽  
pp. 243-263
Author(s):  
Mohd Fadhli Shah Khaidzir ◽  
Ruzy Suliza Hashim ◽  
Noraini Md. Yusof
Keyword(s):  
Critical Role ◽  
Critical Factor ◽  
The Self ◽  
Future Research ◽  
Future Studies ◽  
Place Meaning ◽  
Solid Foundation ◽  
Self Discovery ◽  
Attachment Place

Background and Purpose: The absence of psychogeographical awareness is a critical factor contributing to the lackadaisical attitudes towards the place and its environment. As a result, it enables an individual to fully experience a location, both physically and intellectually, while also gaining a feeling of self-discovery and self-realisation.   Methodology: The purpose of this study was to examine the responses of a group of individuals who participated in a field observation. 40 participants from a Malaysian university's foundation level were brought to Malacca to experience the environment's geographical scenery at their own leisure. The survey data was then manually transcribed and analysed in accordance with the study's aim.   Findings: Interactions with individuals and observation of features in the countryside and urban surroundings enabled participants to go on a psychogeographical journey that influenced their way of thinking and behaving. All participants felt that the journey had influenced their experiences and perspectives on their thinking and behaviour, highlighting the critical role of this notion in establishing the connection between place and self.   Contributions:  The findings of this study provide a solid foundation for future research in the field of psychogeography. The data may be used as a baseline for future studies to determine whether a comparable impact exists in other locations, with or without significant features like those found in Malacca.   Keywords: Psychogeography, place attachment, place meaning, self-discovery, Malacca.   Cite as: Khaidzir, M. F. S., Hashim, R. S., & Md. Yusof, N. (2022). Psychogeographical experience between the self and the place.  Journal of Nusantara Studies, 7(1), 243-263. http://dx.doi.org/10.24200/jonus.vol7iss1pp243-263

Abstract 2620: C1q Exacerbates Mitochondrial Dysfunction Without Activation Of The Terminal Complement In Neonatal Mice With Hypoxic-ischemic Brain Injury.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Vadim S Ten ◽  
Casper Caspersen ◽  
Sivasankar Baalasubramanian ◽  
Paul Morgan ◽  
Marina Botto ◽  
...  
Keyword(s):  
Brain Injury ◽  
Mitochondrial Dysfunction ◽  
Consumption Rate ◽  
Neuronal Damage ◽  
Hypoxic Exposure ◽  
H2o2 Production ◽  
List Type ◽  
O2 Consumption ◽  
Ischemic Brain ◽  
Terminal Complement

Deletion of C1q protects developing brain against hypoxia-ischemia (HI) (Ten V et al; 2005). Hypothesis. C1q mediates HI-brain injury by: Activation of terminal complement or/and Exacerbation of mitochondrial dysfunction. Hypothesis (1) P7 WT (C57Bl/6j) pre-treated with vehicle or sCD59; progenies of C1q+/-, Factor B/C2-/-/-/- inter-mating were subjected to HI: ligation of right carotid artery + hypoxic exposure. At 24 hr of reperfusion the extent of damage, cerebral deposition of C1q, C3, iC3b and C9 were assessed. Hypothesis (2) In C1q-/-and WT mice cerebral ATP-content, mitochondrial O2-consumption rate, H2O2-production and membrane potential (î»m) were studied immediately after HI. At 12 hr electron microscopy for co-staining of C1q and gC1qR/p33 in neurons was performed. WT and C1q-/- cortical and granule neurons in culture were subjected to glutamate or energy failure stress (EFS), glucose deprivation and exposure to 5 mM Na azide. At 24 hr after stress cellular viability, C1q protein and C9 mRNA expression were examined. Results. C1q-/- mice were significantly protected against HI compared to +/+ counterparts. This was associated with robust attenuation of deposition of C3, iC3b and C9 in brain. However, no protection was detected in FB/C2-/ -/ -/ - and sCD59-pretreated mice, although C9-deposition in the injured brain was significantly decreased compared to controls. C1q-/ - mice exhibited a stunning preservation of ATP in the ischemic brain immediately after HI. This was associated with higher O2-consumption rate in state 3 and significantly (two-folds) less production of H2O2 by C1q-/ - mitochondria compared to WT-counterparts without difference in the î»m. In WT-mice HI resulted in intraneuronal, and intramitochondrial accumulation of C1q and gC1qR/p33 only in the ischemic hemisphere. C1q-/ - vs WT cultured neurons were significantly protected against excitotoxic and EFS in the absence of C9-mRNA in cellular lysate. Conclusion. C1q mediates HI-injury. Terminal complement activation has no role in C1q-mediated neuronal damage. The presence of C1q is associated with significantly increased mitochondrial ROS-production in HI-brain. This may represent a novel mechanism for HI-neurodegeneration.

Abstract 396: Inhibition of Prolyl Hydroxylase Domain-containing Protein Downregulates Vascular Angiotensin II Type 1 Receptor

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Toshihiro Ichiki
Keyword(s):  
Cellular Response ◽  
Target Genes ◽  
Interstitial Fibrosis ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Renin Angiotensin System ◽  
Prolyl Hydroxylase ◽  
Ang Ii ◽  
Prolyl Hydroxylase Domain

Background: Prolyl hydroxylase domain-containing protein (PHD) mediates hydroxylation of hypoxia-inducible factor (HIF)-1α and thereby induces proteasomal degradation of HIF-1α. Inhibition of PHD by hypoxia or hypoxia mimetics such as cobalt chloride (CoCl2) stabilizes HIF-1 and increases the expression of target genes such as vascular endothelial growth factor (VEGF). Although hypoxia activates the systemic renin angiotensin system (RAS), the role of PHD in regulating RAS remains unknown. We examined the effect of PHD inhibition on the expression of angiotensin (Ang) II type 1 receptor (AT1R) and its signaling. Methods and Results: Hypoxia (1% O2), CoCl2 (100-300 μmol/L), and dimethyloxalylglycine (0.25-1.0 mmol/L), all known to inhibit PHD, reduced AT1R expression by 37.7±7.6, 39.6±8.4-69.7±9.9, and 13.4±6.1-25.2±7.0%, respectively (p<0.01) in cultured vascular smooth muscle cell. The same stimuli increased the expression of nuclear HIF-1α and VEGF (p<0.05), suggesting that PHD activity is inhibited. Knockdown of PHD2, a major isoform of PHDs, by RNA interference also reduced AT1R expression by 55.3±6.0% (p<0.01). CoCl2 decreased AT1R mRNA through transcriptional and posttranscriptional mechanisms (p<0.01 and <0.05, respectively). CoCl2 and PHD2 knockdown diminished Ang II-induced ERK phosphorylation (P<0.01). Over-expression of the constitutively active HIF-1α did not impact the AT1R gene promoter activity. Oral administration of CoCl2 (14 mg/kg/day) to C57BL/6J mice receiving Ang II infusion (490 ng/kg/min) for 4 weeks significantly reduced the expression of AT1R in the aorta by 60.9±11.3% (p<0.05) and attenuated coronary perivascular fibrosis by 85% (p<0.01) without affecting blood pressure. However, CoCl2 did not affect Ang II-induced renal interstitial fibrosis. Conclusion: PHD inhibition downregulates AT1R expression independently of HIF-1α, reduces the cellular response to Ang II, and attenuates profibrotic effect of Ang II on the coronary arteries. PHD inhibition may be beneficial for the treatment of cardiovascular diseases, in which activation of RAS plays a critical role.

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