Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration

Transcription factor Nrf2 and its repressor Keap1 regulate a network of cytoprotective genes involving more than 1% of the genome, their best known targets being drug-metabolizing and antioxidant genes. Here we demonstrate a novel role for this pathway in directly regulating mitochondrial bioenergetics in murine neurons and embryonic fibroblasts. Loss of Nrf2 leads to mitochondrial depolarisation, decreased ATP levels and impaired respiration, whereas genetic activation of Nrf2 increases the mitochondrial membrane potential and ATP levels, the rate of respiration and the efficiency of oxidative phosphorylation. We further show that Nrf2-deficient cells have increased production of ATP in glycolysis, which is then used by the F1Fo-ATPase for maintenance of the mitochondrial membrane potential. While the levels and in vitro activities of the respiratory complexes are unaffected by Nrf2 deletion, their activities in isolated mitochondria and intact live cells are substantially impaired. In addition, the rate of regeneration of NADH after inhibition of respiration is much slower in Nrf2-knockout cells than in their wild-type counterparts. Taken together, these results show that Nrf2 directly regulates cellular energy metabolism through modulating the availability of substrates for mitochondrial respiration. Our findings highlight the importance of efficient energy metabolism in Nrf2-mediated cytoprotection

The celebrity entrepreneur on television: profile, politics and power

This article examines the rise of the ‘celebrity entrepreneur’ on television through the emergence of the ‘business entertainment format’ and considers the ways in which regular television exposure can be converted into political influence. Within television studies there has been a preoccupation in recent years with how lifestyle and reality formats work to transform ‘ordinary’ people into celebrities. As a result, the contribution of vocationally skilled business professionals to factual entertainment programming has gone almost unnoticed. This article draws on interviews with key media industry professionals and begins by looking at the construction of entrepreneurs as different types of television personalities and how discourses of work, skill and knowledge function in business shows. It then outlines how entrepreneurs can utilize their newly acquired televisual skills to cultivate a wider media profile and secure various forms of political access and influence. Integral to this is the centrality of public relations and media management agencies in shaping media discourses and developing the individual as a ‘brand identity’ that can be used to endorse a range of products or ideas. This has led to policy makers and politicians attempting to mobilize the media profile of celebrity entrepreneurs to reach out and connect with the public on business and enterprise-related issues

Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration

Transcription factor Nrf2 and its repressor Keap1 regulate a network of cytoprotective genes involving more than 1% of the genome, their best known targets being drug-metabolizing and antioxidant genes. Here we demonstrate a novel role for this pathway in directly regulating mitochondrial bioenergetics in murine neurons and embryonic fibroblasts. Loss of Nrf2 leads to mitochondrial depolarisation, decreased ATP levels and impaired respiration, whereas genetic activation of Nrf2 increases the mitochondrial membrane potential and ATP levels, the rate of respiration and the efficiency of oxidative phosphorylation. We further show that Nrf2-deficient cells have increased production of ATP in glycolysis, which is then used by the F1Fo-ATPase for maintenance of the mitochondrial membrane potential. While the levels and in vitro activities of the respiratory complexes are unaffected by Nrf2 deletion, their activities in isolated mitochondria and intact live cells are substantially impaired. In addition, the rate of regeneration of NADH after inhibition of respiration is much slower in Nrf2-knockout cells than in their wild-type counterparts. Taken together, these results show that Nrf2 directly regulates cellular energy metabolism through modulating the availability of substrates for mitochondrial respiration. Our findings highlight the importance of efficient energy metabolism in Nrf2-mediated cytoprotection

Populist communication in the new media environment: a cross-regional comparative perspective

The changing terms of mediation place new demands, opportunities and risks on the performance of the political persona. Visibility has become a double-edged sword, leaving representatives vulnerable to exposure while new tools provide opportunities for emerging entrepreneurial actors. This double risk to elites’ mediated personas—exposure and challenge from entrepreneurs—renders their armour of authenticity dangerously fragile, which nourishes a public sense of being inefficaciously represented. It is this climate in which populism currently flourishes around the globe. Three primary criteria of mediated self-representation by politicians—visibility, authenticity and efficacy—form the focus of this paper: how do populists negotiate such demands in different democratic contexts, and wherein lies the symbiosis between populism and the new media environment suggested by the literature? To answer this, the paper compares two populist cases responding to different democratic contexts: UKIP, a right-wing party from an established democracy (UK), and the Economic Freedom Fighters (EFF), a left-wing party from a transitional democracy (South Africa). The objects of study are disruptive performances by these parties, which are considered emblematic manifestations of populist ideology as they establish a Manichaean relationship between the elite and populist actors who embody the people. The paper introduces disruption as a multi-faceted and significant analytical concept to explain the populist behaviour and strategies that underlie populist parties’ responses to the demands for visibility, authenticity and efficacy that the new media environment places upon political representatives. Using mixed methods with an interpretive focus, the paper paints a rich picture of the contexts, meanings and means of construction of populist performances

The Google voter: search engines and electoral information flows in the new media ecology

This paper explores key Internet search trends for electoral information vis-à-vis the broader media ecology in the UK and the US. An innovative methodology is introduced that maps the informational trajectories of key election events by combining Google Trends data linked to significant news events during the campaigns. While the research found spikes of search that suggested a seemingly trivial event in the US could drive voters to search out deeper information on related policy issues, the study did not find the same phenomenon in the UK. This invites a reflection on the opportunities available to Internet users/voters in the changing informational landscape and how scholars can leverage Google Trends records to better understand how voters seek information in new and evolving media ecologies

Exposing Politicians’ Peccadilloes in Comparative Context: Explaining the Frequency of Political Sex Scandals in Eight Democracies Using Fuzzy Set Qualitative Comparative Analysis

This article was published in the journal Political Communication [© Taylor & Francis Group]. The definitive version is available at: http://dx.doi.org/10.1080/10584609.2012.737434Political sex scandals are largely absent in some democracies but proliferate in others. However, there have so far been few if any comprehensive attempts to document the actual number of sex scandals that have occurred and to explain their presence (and, indeed, absence), and the one study that has (Barker's 1994 study) ended in the early 1990s and had numerous problems in relation to defining and documenting such scandals. Based on extensive research, this article documents the number of sex scandals in eight advanced industrial democracies and tries to explain their occurrence using Charles Ragin's fuzzy set qualitative comparative analysis. The article has three goals: to determine the number of sex scandals in different democracies, explain why this might be, and demonstrate the utility of fuzzy set qualitative case analysis for small- and medium-N comparative research

PINK1 Is Necessary for Long Term Survival and Mitochondrial Function in Human Dopaminergic Neurons

Parkinson's disease (PD) is a common age-related neurodegenerative disease and it is critical to develop models which recapitulate the pathogenic process including the effect of the ageing process. Although the pathogenesis of sporadic PD is unknown, the identification of the mendelian genetic factor PINK1 has provided new mechanistic insights. In order to investigate the role of PINK1 in Parkinson's disease, we studied PINK1 loss of function in human and primary mouse neurons. Using RNAi, we created stable PINK1 knockdown in human dopaminergic neurons differentiated from foetal ventral mesencephalon stem cells, as well as in an immortalised human neuroblastoma cell line. We sought to validate our findings in primary neurons derived from a transgenic PINK1 knockout mouse. For the first time we demonstrate an age dependent neurodegenerative phenotype in human and mouse neurons. PINK1 deficiency leads to reduced long-term viability in human neurons, which die via the mitochondrial apoptosis pathway. Human neurons lacking PINK1 demonstrate features of marked oxidative stress with widespread mitochondrial dysfunction and abnormal mitochondrial morphology. We report that PINK1 plays a neuroprotective role in the mitochondria of mammalian neurons, especially against stress such as staurosporine. In addition we provide evidence that cellular compensatory mechanisms such as mitochondrial biogenesis and upregulation of lysosomal degradation pathways occur in PINK1 deficiency. The phenotypic effects of PINK1 loss-of-function described here in mammalian neurons provides mechanistic insight into the age-related degeneration of nigral dopaminergic neurons seen in PD