p120 catenin is required for the stress response in Drosophila

p120ctn is a ubiquitously expressed core component of cadherin junctions and essential for vertebrate development. Surprisingly, Drosophila p120ctn (dp120ctn) is dispensable for adherens junctions and development, which has discouraged Drosophila researchers from further pursuing the biological role of dp120ctn. Here we demonstrate that dp120ctn loss results in increased heat shock sensitivity and reduced animal lifespan, which are completely rescued by ectopic expression of a dp120ctn-GFP transgene. Transcriptomic analysis revealed multiple relish/NF-κB target genes differentially expressed upon loss of dp120ctn. Importantly, this aberrant gene expression was rescued by overexpression of dp120ctn-GFP or heterozygosity for relish. Our results uncover a novel role for dp120ctn in the regulation of animal stress response and immune signalling. This may represent an ancient role of p120ctn and can influence further studies in Drosophila and mammals

The role of mitochondrial ROS in the aging brain

The brain is the most complex human organ, consuming more energy than any other tissue in proportion to its size. It relies heavily on mitochondria to produce energy and is made up of mitotic and postmitotic cells that need to closely coordinate their metabolism to maintain essential bodily functions. During aging, damaged mitochondria that produce less ATP and more reactive oxygen species (ROS) accumulate. The current consensus is that ROS cause oxidative stress, damaging mitochondria and resulting in an energetic crisis that triggers neurodegenerative diseases and accelerates aging. However, in model organisms, increasing mitochondrial ROS (mtROS) in the brain extends lifespan, suggesting that ROS may participate in signaling that protects the brain. Here, we summarize the mechanisms by which mtROS are produced at the molecular level, how different brain cells and regions produce different amounts of mtROS, and how mtROS levels change during aging. Finally, we critically discuss the possible roles of ROS in aging as signaling molecules and damaging agents, addressing whether age‐associated increases in mtROS are a cause or a consequence of aging

Transformed epithelia trigger non-tissue-autonomous tumor suppressor response by adipocytes via activation of toll and Eiger/TNF signaling

High tumor burden is associated with increased levels of circulating inflammatory cytokines that influence the pathophysiology of the tumor and its environment. The cellular and molecular events mediating the organismal response to a growing tumor are poorly understood. Here, we report a bidirectional crosstalk between epithelial tumors and the fat body—a peripheral immune tissue—in Drosophila. Tumors trigger a systemic immune response through activation of Eiger/TNF signaling, which leads to Toll pathway upregulation in adipocytes. Reciprocally, Toll elicits a non-tissue-autonomous program in adipocytes, which drives tumor cell death. Hemocytes play a critical role in this system by producing the ligands Spätzle and Eiger, which are required for Toll activation in the fat body and tumor cell death. Altogether, our results provide a paradigm for a long-range tumor suppression function of adipocytes in Drosophila, which may represent an evolutionarily conserved mechanism in the organismal response to solid tumors

Modelling tumourigenesis and the stress response in Drosophila melanogaster

Abstract available: p. 2

A beginner’s guide to supervising a PhD researcher

This beginner’s guide to supervision has been created for anyone who supports postgraduate researchers (PGRs) with any aspect of their research or the completion of their degree. The supervision of PGRs is a complex and time-consuming job, with a high degree of responsibility. Good supervision is a key component of PGR success and is vital to the health of our research as a nation as well as the health of our individual researchers. In the recent research literature, supervision has been shown to impact on PhD completion time, retention of students, their success, their perceptions of the value of the PhD, their mental health and well-being and their career choice. In acknowledgement, the UKRI statement of Expectations for Postgraduate Training states that “Research Organisations are expected to provide excellent standards of supervision, management and mentoring…” and the UK’s Quality Assurance Agency states that therefore “Supervisors should be provided with sufficient time, support and opportunities to develop and maintain their supervisory practice”. Noting that “supervisors represent the most important external influence in the learning and development that occurs in students’ training” the International Union of Biochemistry and Molecular Biology’s Committee on Education details interpersonal responsibilities of the supervisor that cover the need to work as partners, see the student as a whole person, be aware of power imbalance and develop strategies for the resolution of relationship difficulties, as well as giving academic and career support

Mitochondrial ROS production correlates with, but does not directly regulate lifespan in drosophila

The Mitochondrial Free Radical Theory of Aging (MFRTA) is currently one of the most widely accepted theories used to explain aging. From MFRTA three basic predictions can be made: long-lived individuals or species should produce fewer mitochondrial Reactive Oxygen Species (mtROS) than short-lived individuals or species; a decrease in mtROS production will increase lifespan; and an increase in mtROS production will decrease lifespan. It is possible to add a further fourth prediction: if ROS is controlling longevity separating these parameters through selection would be impossible. These predictions have been tested in Drosophila melanogaster. Firstly, we studied levels of mtROS production and lifespan of three wild-type strains of Drosophila, Oregon R, Canton S and Dahomey. Oregon R flies live the longest and produce significantly fewer mtROS than both Canton S and Dahomey. These results are therefore in accordance with the first prediction. A new transgenic Drosophila model expressing the Ciona intestinalis Alternative Oxidase (AOX) was used to test the second prediction. In fungi and plants, AOX expression regulates both free radical production and lifespan. In Drosophila, AOX expression decreases mtROS production, but does not increase lifespan. This result contradicts the second prediction of MFRTA. The third prediction was tested in flies mutant for the gene dj-1β. These flies are characterized by an age-associated decline in locomotor function and increased levels of mtROS production. Nevertheless, dj-1β mutant flies do not display decreased lifespan, which again is in contradiction with MFRTA. In our final experiment we utilized flies with DAH mitochondrial DNA in an OR nuclear background, and OR mitochondrial DNA in DAH nuclear background. From this, Mitochondrial DNA does not control free radical production, but it does determine longevity of females independently of mtROS production. In summary, these results do not systematically support the predictions of the MFRTA. Accordingly, MFRTA should be revised to accommodate these findings

Mitochondrial ROS production correlates with, but does not directly regulate lifespan in drosophila

This is an open-access article distributed under the terms of the Creative Commons Attribution License.The Mitochondrial Free Radical Theory of Aging (MFRTA) is currently one of the most widely accepted theories used to explain aging. From MFRTA three basic predictions can be made: long-lived individuals or species should produce fewer mitochondrial Reactive Oxygen Species (mtROS) than short-lived individuals or species; a decrease in mtROS production will increase lifespan; and an increase in mtROS production will decrease lifespan. It is possible to add a further fourth prediction: if ROS is controlling longevity separating these parameters through selection would be impossible. These predictions have been tested in Drosophila melanogaster. Firstly, we studied levels of mtROS production and lifespan of three wild-type strains of Drosophila, Oregon R, Canton S and Dahomey. Oregon R flies live the longest and produce significantly fewer mtROS than both Canton S and Dahomey. These results are therefore in accordance with the first prediction. A new transgenic Drosophila model expressing the Ciona intestinalis Alternative Oxidase (AOX) was used to test the second prediction. In fungi and plants, AOX expression regulates both free radical production and lifespan. In Drosophila, AOX expression decreases mtROS production, but does not increase lifespan. This result contradicts the second prediction of MFRTA. The third prediction was tested in flies mutant for the gene dj-1β. These flies are characterized by an age-associated decline in locomotor function and increased levels of mtROS production. Nevertheless, dj-1β mutant flies do not display decreased lifespan, which again is in contradiction with MFRTA. In our final experiment we utilized flies with DAH mitochondrial DNA in an OR nuclear background, and OR mitochondrial DNA in DAH nuclear background. From this, Mitochondrial DNA does not control free radical production, but it does determine longevity of females independently of mtROS production. In summary, these results do not systematically support the predictions of the MFRTA. Accordingly, MFRTA should be revised to accommodate these findings.Our work is supported by funding from the Academy of Finland, Tampere Hospital Medical Research Fund, Juselius Foundation, the European Union and EMBO (long-term fellowship to AS).Peer Reviewe

Oxidation of p62 as an evolutionary adaptation to promote autophagy in stress conditions

Ageing and age-related diseases are characterised by increased oxidative and proteotoxic stress, which results in negative effects on cell function and survival. The cell possesses several mechanisms to deal with damaged proteins, including degradation via macroautophagy (hereafter called autophagy). This essential cellular pathway is conserved from yeast to humans and it is well established that its impairment reduces lifespan in multiple model organisms, including worms, flies and mice. In our study, recently published in Nature Communications, we asked if longer lifespan characteristic of higher organisms is the result of evolutionary adaptations to the autophagy machinery. We found that the autophagy receptor p62 can be oxidised leading to its oligomerisation which ultimately promotes autophagy. However this mechanism, present in vertebrates, has been acquired late in evolution. We propose that the ability of p62 to sense reactive oxygen species (ROS) via oxidation, and potentially other similar modifications, may have evolved in higher organisms and contributed to their increased lifespan. Indeed, impairment of this process could result in age-related neurodegeneration in humans

Essential Physiological Differences Characterize Short- and Long-Lived Strains of Drosophila melanogaster

Aging is a multifactorial process which affects all animals. Aging as a result of damage accumulation is the most accepted explanation but the proximal causes remain to be elucidated. There is also evidence indicating that aging has an important genetic component. Animal species age at different rates and specific signaling pathways, such as insulin/insulin-like growth factor, can regulate life span of individuals within a species by reprogramming cells in response to environmental changes. Here, we use an unbiased approach to identify novel factors that regulate life span in Drosophila melanogaster. We compare the transcriptome and metabolome of two wild-type strains used widely in aging research: short-lived Dahomey and long-lived Oregon R flies. We found that Dahomey flies carry several traits associated with short-lived individuals and species such as increased lipoxidative stress, decreased mitochondrial gene expression, and increased Target of Rapamycin signaling. Dahomey flies also have upregulated octopamine signaling known to stimulate foraging behavior. Accordingly, we present evidence that increased foraging behavior, under laboratory conditions where nutrients are in excess increases damage generation and accelerates aging. In summary, we have identified several new pathways, which influence longevity highlighting the contribution and importance of the genetic component of aging.This work was supported by the European Research Council (260632 - ComplexI&Aging to A.S.); the Academy of Finland (252048 to A.S); the Biotechnology and Biological Sciences Research Council ( BB/M023311/1 to A.S.); the Centre for International Mobility (CIMO) (TM-12- 8391 and TM-13-8919 to N.G.); the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (PI14/00328 to R.P. and PI17/01286 to P.N.); the Autonomous Government of Catalonia (2017SGR696 and SLT002/16/00250 to R.P.); the Ministry of Education and Science of Ukraine (grant number 0117U006426 to O.L.); FEDER funds from the European Union (“A way to build Europe” to R.P.); and the Doctoral Programme in Medicine and Life Sciences of University of Tampere (to T.R). R.S is a Sir Henry Wellcome Postdoctoral Fellow funded by Wellcome (204715/Z/16/Z

Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis.

Cellular homoeostatic pathways such as macroautophagy (hereinafter autophagy) are regulated by basic mechanisms that are conserved throughout the eukaryotic kingdom. However, it remains poorly understood how these mechanisms further evolved in higher organisms. Here we describe a modification in the autophagy pathway in vertebrates, which promotes its activity in response to oxidative stress. We have identified two oxidation-sensitive cysteine residues in a prototypic autophagy receptor SQSTM1/p62, which allow activation of pro-survival autophagy in stress conditions. The Drosophila p62 homologue, Ref(2)P, lacks these oxidation-sensitive cysteine residues and their introduction into the protein increases protein turnover and stress resistance of flies, whereas perturbation of p62 oxidation in humans may result in age-related pathology. We propose that the redox-sensitivity of p62 may have evolved in vertebrates as a mechanism that allows activation of autophagy in response to oxidative stress to maintain cellular homoeostasis and increase cell survival