Publications by authors named "Didac Carmona-Gutierrez"

87 Publications

Assessing autophagic flux in yeast.

Methods Cell Biol 2021 20;164:73-94. Epub 2020 Nov 20.

Institute for Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria. Electronic address:

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http://dx.doi.org/10.1016/bs.mcb.2020.10.014DOI Listing
November 2020

Dietary spermidine improves cognitive function.

Cell Rep 2021 Apr;35(2):108985

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, 6020 Innsbruck, Austria.

Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.
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http://dx.doi.org/10.1016/j.celrep.2021.108985DOI Listing
April 2021

Spermidine supplementation in rare translation-associated disorders.

Cell Stress 2021 Mar 8;5(3):29-32. Epub 2021 Mar 8.

Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.

The polyamine spermidine is essential for protein translation in eukaryotes, both as a substrate for the hypusination of the translation initiation factor eIF5A as well as general translational fidelity. Dwindling spermidine levels during aging have been implicated in reduced immune cell function through insufficient eIF5A hypusination, which can be restored by external supplementation. Recent findings characterize a group of novel Mendelian disorders linked to missense and nonsense variants that cause protein translation defects. In model organisms that recapitulate these mutations, spermidine supplementation was able to alleviate at least some of the concomitant protein translation defects. Here, we discuss the role of spermidine in protein translation and possible therapeutic avenues for translation-associated disorders.
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http://dx.doi.org/10.15698/cst2021.03.243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921850PMC
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Isobacachalcone induces autophagy and improves the outcome of immunogenic chemotherapy.

Cell Death Dis 2020 11 26;11(11):1015. Epub 2020 Nov 26.

Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.

A number of natural plant products have a long-standing history in both traditional and modern medical applications. Some secondary metabolites induce autophagy and mediate autophagy-dependent healthspan- and lifespan-extending effects in suitable mouse models. Here, we identified isobacachalcone (ISO) as a non-toxic inducer of autophagic flux that acts on human and mouse cells in vitro, as well as mouse organs in vivo. Mechanistically, ISO inhibits AKT as well as, downstream of AKT, the mechanistic target of rapamycin complex 1 (mTORC1), coupled to the activation of the pro-autophagic transcription factors EB (TFEB) and E3 (TFE3). Cells equipped with a constitutively active AKT mutant failed to activate autophagy. ISO also stimulated the AKT-repressible activation of all three arms of the unfolded stress response (UPR), including the PERK-dependent phosphorylation of eukaryotic initiation factor 2α (eIF2α). Knockout of TFEB and/or TFE3 blunted the UPR, while knockout of PERK or replacement of eIF2α by a non-phosphorylable mutant reduced TFEB/TFE3 activation and autophagy induced by ISO. This points to crosstalk between the UPR and autophagy. Of note, the administration of ISO to mice improved the efficacy of immunogenic anticancer chemotherapy. This effect relied on an improved T lymphocyte-dependent anticancer immune response and was lost upon constitutive AKT activation in, or deletion of the essential autophagy gene Atg5 from, the malignant cells. In conclusion, ISO is a bioavailable autophagy inducer that warrants further preclinical characterization.
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http://dx.doi.org/10.1038/s41419-020-03226-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690654PMC
November 2020

Nutritional Aspects of Spermidine.

Annu Rev Nutr 2020 09 7;40:135-159. Epub 2020 Jul 7.

Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; email:

Natural polyamines (spermidine and spermine) are small, positively charged molecules that are ubiquitously found within organisms and cells. They exert numerous (intra)cellular functions and have been implicated to protect against several age-related diseases. Although polyamine levels decline in a complex age-dependent, tissue-, and cell type-specific manner, they are maintained in healthy nonagenarians and centenarians. Increased polyamine levels, including through enhanced dietary intake, have been consistently linked to improved health and reduced overall mortality. In preclinical models, dietary supplementation with spermidine prolongs life span and health span. In this review, we highlight salient aspects of nutritional polyamine intake and summarize the current knowledge of organismal and cellular uptake and distribution of dietary (and gastrointestinal) polyamines and their impact on human health. We further summarize clinical and epidemiological studies of dietary polyamines.
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http://dx.doi.org/10.1146/annurev-nutr-120419-015419DOI Listing
September 2020

Fungal infections in humans: the silent crisis.

Microb Cell 2020 Jun 1;7(6):143-145. Epub 2020 Jun 1.

Institute for Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.

Annually, over 150 million severe cases of fungal infections occur worldwide, resulting in approximately 1.7 million deaths per year. Alarmingly, these numbers are continuously on the rise with a number of social and medical developments during the past decades that have abetted the spread of fungal infections. Additionally, the long-term therapeutic application and prophylactic use of antifungal drugs in high-risk patients have promoted the emergence of (multi)drug-resistant fungi, including the extremely virulent strain . Hence, fungal infections are already a global threat that is becoming increasingly severe. In this article, we underline the importance of more and effective research to counteract fungal infections and their consequences.
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http://dx.doi.org/10.15698/mic2020.06.718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278517PMC
June 2020

Digesting the crisis: autophagy and coronaviruses.

Microb Cell 2020 May 4;7(5):119-128. Epub 2020 May 4.

Institute for Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.

Autophagy is a catabolic pathway with multifaceted roles in cellular homeostasis. This process is also involved in the antiviral response at multiple levels, including the direct elimination of intruding viruses (virophagy), the presentation of viral antigens, the fitness of immune cells, and the inhibition of excessive inflammatory reactions. In line with its central role in immunity, viruses have evolved mechanisms to interfere with or to evade the autophagic process, and in some cases, even to harness autophagy or constituents of the autophagic machinery for their replication. Given the devastating consequences of the current COVID-19 pandemic, the question arises whether manipulating autophagy might be an expedient approach to fight the novel coronavirus SARS-CoV-2. In this piece, we provide a short overview of the evidence linking autophagy to coronaviruses and discuss whether such links may provide actionable targets for therapeutic interventions.
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http://dx.doi.org/10.15698/mic2020.05.715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199282PMC
May 2020

Transcriptional and epigenetic control of regulated cell death in yeast.

Int Rev Cell Mol Biol 2020 13;352:55-82. Epub 2020 Jan 13.

Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria. Electronic address:

Unicellular organisms like yeast can undergo controlled demise in a manner that is partly reminiscent of mammalian cell death. This is true at the levels of both mechanistic and functional conservation. Yeast offers the combination of unparalleled genetic amenability and a comparatively simple biology to understand both the regulation and evolution of cell death. In this minireview, we address the capacity of the nucleus as a regulatory hub during yeast regulated cell death (RCD), which is becoming an increasingly central question in yeast RCD research. In particular, we explore and critically discuss the available data on stressors and signals that specifically impinge on the nucleus. Moreover, we also analyze the current knowledge on nuclear factors as well as on transcriptional control and epigenetic events that orchestrate yeast RCD. Altogether we conclude that the functional significance of the nucleus for yeast RCD in undisputable, but that further exploration beyond correlative work is necessary to disentangle the role of nuclear events in the regulatory network.
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http://dx.doi.org/10.1016/bs.ircmb.2019.12.003DOI Listing
December 2020

A discovery platform for the identification of caloric restriction mimetics with broad health-improving effects.

Autophagy 2020 01 7;16(1):188-189. Epub 2019 Nov 7.

Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.

The age-related decline in organismal fitness results in vulnerability to pathologies and eventual lethal decay. One way to counteract cellular aging and to delay and/or prevent the onset of age-related maladies is the reduction of calorie intake or the institution of fasting regimens. Caloric restriction mimetics (CRMs) have the ability to imitate the health-promoting and lifespan-extending effects of caloric restriction without the need for dietary restriction. CRMs induce an increase in autophagic flux in response to the deacetylation of cellular proteins in the absence of cytotoxicity. Here we report the development of a high-throughput discovery platform for novel CRMs that uses systems biology approaches, in vitro validation and functional tests employing in vivo disease models. This workflow led to the identification of 3,4-dimethoxychalcone (3,4-DC) as a novel CRM that stimulated TFEB (transcription factor EB)- and TFE3 (transcription factor E3)-dependent macroautophagy/autophagy. 3,4-DC showed cardioprotective effects and stimulated anticancer immunosurveillance in the context of immunogenic chemotherapy.
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http://dx.doi.org/10.1080/15548627.2019.1688984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984457PMC
January 2020

3,4-Dimethoxychalcone induces autophagy through activation of the transcription factors TFE3 and TFEB.

EMBO Mol Med 2019 11 14;11(11):e10469. Epub 2019 Oct 14.

Gustave Roussy Cancer Campus, Villejuif, France.

Caloric restriction mimetics (CRMs) are natural or synthetic compounds that mimic the health-promoting and longevity-extending effects of caloric restriction. CRMs provoke the deacetylation of cellular proteins coupled to an increase in autophagic flux in the absence of toxicity. Here, we report the identification of a novel candidate CRM, namely 3,4-dimethoxychalcone (3,4-DC), among a library of polyphenols. When added to several different human cell lines, 3,4-DC induced the deacetylation of cytoplasmic proteins and stimulated autophagic flux. At difference with other well-characterized CRMs, 3,4-DC, however, required transcription factor EB (TFEB)- and E3 (TFE3)-dependent gene transcription and mRNA translation to trigger autophagy. 3,4-DC stimulated the translocation of TFEB and TFE3 into nuclei both in vitro and in vivo, in hepatocytes and cardiomyocytes. 3,4-DC induced autophagy in vitro and in mouse organs, mediated autophagy-dependent cardioprotective effects, and improved the efficacy of anticancer chemotherapy in vivo. Altogether, our results suggest that 3,4-DC is a novel CRM with a previously unrecognized mode of action.
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http://dx.doi.org/10.15252/emmm.201910469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835206PMC
November 2019

4,4'Dimethoxychalcone: a natural flavonoid that promotes health through autophagy-dependent and -independent effects.

Autophagy 2019 09 28;15(9):1662-1664. Epub 2019 Jun 28.

f Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers , INSERM U 1138, Paris , France.

The age-induced deterioration of the organism results in detrimental and ultimately lethal pathologies. The process of aging itself involves a plethora of different mechanisms that should be subverted concurrently to delay and/or prevent age-related maladies. We have identified a natural compound, 4,4'-dimethoxychalcone (DMC), which promotes longevity in yeast, worms and flies, and protects mice from heart injury and liver toxicity. Interestingly, both the DMC-mediated lifespan extension and the cardioprotection depend on macroautophagy/autophagy whereas hepatoprotection does not. DMC induces autophagy by inhibiting specific GATA transcription factors (TFs), independently of the TORC1 kinase pathway. The autophagy-independent beneficial effects of DMC might involve its antioxidative properties. DMC treatment results in a phylogenetically conserved, systemic impact on the metabolome, which is most prominently characterized by changes in cellular amino acid composition. Altogether, DMC exerts multiple, geroprotective effects by igniting distinct pathways, and thus represents a potential pharmacological agent that delays aging through multipronged effects.
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http://dx.doi.org/10.1080/15548627.2019.1632623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693465PMC
September 2019

Acetyl-CoA carboxylase 1-dependent lipogenesis promotes autophagy downstream of AMPK.

J Biol Chem 2019 08 17;294(32):12020-12039. Epub 2019 Jun 17.

Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; Central Lab Gracia, NAWI Graz, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria. Electronic address:

Autophagy, a membrane-dependent catabolic process, ensures survival of aging cells and depends on the cellular energetic status. Acetyl-CoA carboxylase 1 (Acc1) connects central energy metabolism to lipid biosynthesis and is rate-limiting for the synthesis of lipids. However, it is unclear how lipogenesis and its metabolic consequences affect autophagic activity. Here, we show that in aging yeast, autophagy levels highly depend on the activity of Acc1. Constitutively active Acc1 ( ) or a deletion of the Acc1 negative regulator, Snf1 (yeast AMPK), shows elevated autophagy levels, which can be reversed by the Acc1 inhibitor soraphen A. Vice versa, pharmacological inhibition of Acc1 drastically reduces cell survival and results in the accumulation of Atg8-positive structures at the vacuolar membrane, suggesting late defects in the autophagic cascade. As expected, cells exhibit a reduction in acetate/acetyl-CoA availability along with elevated cellular lipid content. However, concomitant administration of acetate fails to fully revert the increase in autophagy exerted by Instead, administration of oleate, while mimicking constitutively active Acc1 in WT cells, alleviates the vacuolar fusion defects induced by Acc1 inhibition. Our results argue for a largely lipid-dependent process of autophagy regulation downstream of Acc1. We present a versatile genetic model to investigate the complex relationship between acetate metabolism, lipid homeostasis, and autophagy and propose Acc1-dependent lipogenesis as a fundamental metabolic path downstream of Snf1 to maintain autophagy and survival during cellular aging.
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http://dx.doi.org/10.1074/jbc.RA118.007020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690696PMC
August 2019

Targeting GATA transcription factors - a novel strategy for anti-aging interventions?

Microb Cell 2019 May 6;6(5):212-216. Epub 2019 May 6.

Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.

GATA transcription factors (TFs) are a conserved family of zinc-finger TFs that fulfill diverse functions across eukaryotes. Accumulating evidence suggests that GATA TFs also play a role in lifespan regulation. In a recent study, we have identified a natural compound, 4,4' dimethoxychalcone (DMC) that extends lifespan depending on reduced activity of distinct GATA TFs. Prolonged lifespan by DMC treatment depends on autophagy, a protective cellular self-cleaning mechanism. In yeast, DMC reduces the activity of the GATA TF Gln3 and, at the same time, deletion of GLN3 increases autophagy levels during cellular aging per se. Here, we examine current data on the involvement of GATA TFs in the regulation of both autophagy and lifespan in different organisms and explore, if GATA TFs are suitable targets for anti-aging interventions.
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http://dx.doi.org/10.15698/mic2019.05.676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506692PMC
May 2019

Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential.

Cell Metab 2019 03;29(3):592-610

Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, Paris, France; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden; Center of Systems Medicine, Chinese Academy of Science, Suzhou, China. Electronic address:

The increase in life expectancy has boosted the incidence of age-related pathologies beyond social and economic sustainability. Consequently, there is an urgent need for interventions that revert or at least prevent the pathogenic age-associated deterioration. The permanent or periodic reduction of calorie intake without malnutrition (caloric restriction and fasting) is the only strategy that reliably extends healthspan in mammals including non-human primates. However, the strict and life-long compliance with these regimens is difficult, which has promoted the emergence of caloric restriction mimetics (CRMs). We define CRMs as compounds that ignite the protective pathways of caloric restriction by promoting autophagy, a cytoplasmic recycling mechanism, via a reduction in protein acetylation. Here, we describe the current knowledge on molecular, cellular, and organismal effects of known and putative CRMs in mice and humans. We anticipate that CRMs will become part of the pharmacological armamentarium against aging and age-related cardiovascular, neurodegenerative, and malignant diseases.
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http://dx.doi.org/10.1016/j.cmet.2019.01.018DOI Listing
March 2019

The flavonoid 4,4'-dimethoxychalcone promotes autophagy-dependent longevity across species.

Nat Commun 2019 02 19;10(1):651. Epub 2019 Feb 19.

Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.

Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4'-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.
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http://dx.doi.org/10.1038/s41467-019-08555-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381180PMC
February 2019

Autophagy in Cardiovascular Aging.

Circ Res 2018 09;123(7):803-824

Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France (G.K.).

Cardiovascular diseases are the most prominent maladies in aging societies. Indeed, aging promotes the structural and functional declines of both the heart and the blood circulation system. In this review, we revise the contribution of known longevity pathways to cardiovascular health and delineate the possibilities to interfere with them. In particular, we evaluate autophagy, the intracellular catabolic recycling system associated with life- and health-span extension. We present genetic models, pharmacological interventions, and dietary strategies that block, reduce, or enhance autophagy upon age-related cardiovascular deterioration. Caloric restriction or caloric restriction mimetics like metformin, spermidine, and rapamycin (all of which trigger autophagy) are among the most promising cardioprotective interventions during aging. We conclude that autophagy is a fundamental process to ensure cardiac and vascular health during aging and outline its putative therapeutic importance.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.312208DOI Listing
September 2018

Spermidine reduces cancer-related mortality in humans.

Autophagy 2019 02 29;15(2):362-365. Epub 2018 Oct 29.

b INSERM, U1138 , Paris , France.

A recent prospective epidemiological study suggested that an increase in the nutritional uptake of the natural polyamine spermidine is associated with reduced overall and cancer-specific mortality. Here, we speculate through which mechanisms spermidine might exert such oncopreventive effects. ACLY, ATP citrate lyase; ATG, autophagy-related gene; CoA, coenzyme A; NSCLC, non-small cell lung cancer.
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http://dx.doi.org/10.1080/15548627.2018.1539592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333461PMC
February 2019

Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans?

Autophagy 2019 01 11;15(1):165-168. Epub 2018 Oct 11.

c Equipe 11 labellisée Ligue contre le Cancer , Centre de Recherche des Cordeliers, INSERM U , Paris , France.

Spermidine is a natural polyamine that stimulates cytoprotective macroautophagy/autophagy. External supplementation of spermidine extends lifespan and health span across species, including in yeast, nematodes, flies and mice. In humans, spermidine levels decline with aging, and a possible connection between reduced endogenous spermidine concentrations and age-related deterioration has been suggested. Recent epidemiological data support this notion, showing that an increased uptake of this polyamine with spermidine-rich food diminishes overall mortality associated with cardiovascular diseases and cancer. Here, we discuss nutritional and other possible routes to counteract the age-mediated decline of spermidine levels.
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http://dx.doi.org/10.1080/15548627.2018.1530929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287690PMC
January 2019

Studying Huntington's Disease in Yeast: From Mechanisms to Pharmacological Approaches.

Front Mol Neurosci 2018 4;11:318. Epub 2018 Sep 4.

Institute of Molecular Biosciences, University of Graz, Graz, Austria.

Huntington's disease (HD) is a neurodegenerative disorder that leads to progressive neuronal loss, provoking impaired motor control, cognitive decline, and dementia. So far, HD remains incurable, and available drugs are effective only for symptomatic management. HD is caused by a mutant form of the huntingtin protein, which harbors an elongated polyglutamine domain and is highly prone to aggregation. However, many aspects underlying the cytotoxicity of mutant huntingtin (mHTT) remain elusive, hindering the efficient development of applicable interventions to counteract HD. An important strategy to obtain molecular insights into human disorders in general is the use of eukaryotic model organisms, which are easy to genetically manipulate and display a high degree of conservation regarding disease-relevant cellular processes. The budding yeast has a long-standing and successful history in modeling a plethora of human maladies and has recently emerged as an effective tool to study neurodegenerative disorders, including HD. Here, we summarize some of the most important contributions of yeast to HD research, specifically concerning the elucidation of mechanistic features of mHTT cytotoxicity and the potential of yeast as a platform to screen for pharmacological agents against HD.
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http://dx.doi.org/10.3389/fnmol.2018.00318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131589PMC
September 2018

Spermidine delays aging in humans.

Aging (Albany NY) 2018 Aug;10(8):2209-2211

Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.

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http://dx.doi.org/10.18632/aging.101517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128428PMC
August 2018

Yeast as a tool to identify anti-aging compounds.

FEMS Yeast Res 2018 09;18(6)

Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, 8010, Austria.

In the search for interventions against aging and age-related diseases, biological screening platforms are indispensable tools to identify anti-aging compounds among large substance libraries. The budding yeast, Saccharomyces cerevisiae, has emerged as a powerful chemical and genetic screening platform, as it combines a rapid workflow with experimental amenability and the availability of a wide range of genetic mutant libraries. Given the amount of conserved genes and aging mechanisms between yeast and human, testing candidate anti-aging substances in yeast gene-deletion or overexpression collections, or de novo derived mutants, has proven highly successful in finding potential molecular targets. Yeast-based studies, for example, have led to the discovery of the polyphenol resveratrol and the natural polyamine spermidine as potential anti-aging agents. Here, we present strategies for pharmacological anti-aging screens in yeast, discuss common pitfalls and summarize studies that have used yeast for drug discovery and target identification.
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http://dx.doi.org/10.1093/femsyr/foy020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001894PMC
September 2018

Microbial wars: Competition in ecological niches and within the microbiome.

Microb Cell 2018 May 7;5(5):215-219. Epub 2018 May 7.

Institute of Molecular Biosciences, University of Graz, Graz, Austria.

Many microbial communities live in highly competitive surroundings, in which the fight for resources determines their survival and genetic persistence. Humans live in a close relationship with microbial communities, which includes the health- and disease-determining interactions with our microbiome. Accordingly, the understanding of microbial competitive activities are essential at physiological and pathophysiological levels. Here we provide a brief overview on microbial competition and discuss some of its roles and consequences that directly affect humans.
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http://dx.doi.org/10.15698/mic2018.05.628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961915PMC
May 2018

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Cell Death Differ 2018 03 23;25(3):486-541. Epub 2018 Jan 23.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
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http://dx.doi.org/10.1038/s41418-017-0012-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864239PMC
March 2018

Guidelines and recommendations on yeast cell death nomenclature.

Microb Cell 2018 Jan 1;5(1):4-31. Epub 2018 Jan 1.

Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy.

Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cel-lular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the defi-nition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differ-ential definition of terms including apoptosis, regulated necrosis, and autophagic cell death, as we refer to additional cell death rou-tines that are relevant for the biology of (at least some species of) yeast. As this area of investigation advances rapidly, changes and extensions to this set of recommendations will be implemented in the years to come. Nonetheless, we strongly encourage the au-thors, reviewers and editors of scientific articles to adopt these collective standards in order to establish an accurate framework for yeast cell death research and, ultimately, to accelerate the pro-gress of this vibrant field of research.
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http://dx.doi.org/10.15698/mic2018.01.607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772036PMC
January 2018

Mitochondrial energy metabolism is required for lifespan extension by the spastic paraplegia-associated protein spartin.

Microb Cell 2017 Nov 30;4(12):411-422. Epub 2017 Nov 30.

BioTechMed Graz, Graz, Austria.

Hereditary spastic paraplegias, a group of neurodegenerative disorders, can be caused by loss-of-function mutations in the protein spartin. However, the physiological role of spartin remains largely elusive. Here we show that heterologous expression of human or spartin extends chronological lifespan of yeast, reducing age-associated ROS production, apoptosis, and necrosis. We demonstrate that spartin localizes to the proximity of mitochondria and physically interacts with proteins related to mitochondrial and respiratory metabolism. Interestingly, Nde1, the mitochondrial external NADH dehydrogenase, and Pda1, the core enzyme of the pyruvate dehydrogenase complex, are required for spartin-mediated cytoprotection. Furthermore, spartin interacts with the glycolysis enhancer phospo-fructo-kinase-2,6 (Pfk26) and is sufficient to complement for -deficiency at least in early aging. We conclude that mitochondria-related energy metabolism is crucial for spartin's vital function during aging and uncover a network of specific interactors required for this function.
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http://dx.doi.org/10.15698/mic2017.12.603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722644PMC
November 2017

Diacylglycerol triggers Rim101 pathway-dependent necrosis in yeast: a model for lipotoxicity.

Cell Death Differ 2018 03 11;25(4):767-783. Epub 2017 Dec 11.

Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, 8010, Austria.

The loss of lipid homeostasis can lead to lipid overload and is associated with a variety of disease states. However, little is known as to how the disruption of lipid regulation or lipid overload affects cell survival. In this study we investigated how excess diacylglycerol (DG), a cardinal metabolite suspected to mediate lipotoxicity, compromises the survival of yeast cells. We reveal that increased DG achieved by either genetic manipulation or pharmacological administration of 1,2-dioctanoyl-sn-glycerol (DOG) triggers necrotic cell death. The toxic effects of DG are linked to glucose metabolism and require a functional Rim101 signaling cascade involving the Rim21-dependent sensing complex and the activation of a calpain-like protease. The Rim101 cascade is an established pathway that triggers a transcriptional response to alkaline or lipid stress. We propose that the Rim101 pathway senses DG-induced lipid perturbation and conducts a signaling response that either facilitates cellular adaptation or triggers lipotoxic cell death. Using established models of lipotoxicity, i.e., high-fat diet in Drosophila and palmitic acid administration in cultured human endothelial cells, we present evidence that the core mechanism underlying this calpain-dependent lipotoxic cell death pathway is phylogenetically conserved.
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http://dx.doi.org/10.1038/s41418-017-0014-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864183PMC
March 2018

- a new journal for cellular pathophysiology.

Cell Stress 2017 Oct 1;1(1):1-3. Epub 2017 Oct 1.

Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.

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http://dx.doi.org/10.15698/cst2017.10.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551653PMC
October 2017

The Coordinated Action of Calcineurin and Cathepsin D Protects Against α-Synuclein Toxicity.

Front Mol Neurosci 2017 30;10:207. Epub 2017 Jun 30.

Institute of Molecular Biosciences, University of GrazGraz, Austria.

The degeneration of dopaminergic neurons during Parkinson's disease (PD) is intimately linked to malfunction of α-synuclein (αSyn), the main component of the proteinaceous intracellular inclusions characteristic for this pathology. The cytotoxicity of αSyn has been attributed to disturbances in several biological processes conserved from yeast to humans, including Ca homeostasis, general lysosomal function and autophagy. However, the precise sequence of events that eventually results in cell death remains unclear. Here, we establish a connection between the major lysosomal protease cathepsin D (CatD) and the Ca/calmodulin-dependent phosphatase calcineurin. In a yeast model for PD, high levels of human αSyn triggered cytosolic acidification and reduced vacuolar hydrolytic capacity, finally leading to cell death. This could be counteracted by overexpression of yeast CatD (Pep4), which re-installed pH homeostasis and vacuolar proteolytic function, decreased αSyn oligomers and aggregates, and provided cytoprotection. Interestingly, these beneficial effects of Pep4 were independent of autophagy. Instead, they required functional calcineurin signaling, since deletion of calcineurin strongly reduced both the proteolytic activity of endogenous Pep4 and the cytoprotective capacity of overexpressed Pep4. Calcineurin contributed to proper endosomal targeting of Pep4 to the vacuole and the recycling of the Pep4 sorting receptor Pep1 from prevacuolar compartments back to the trans-Golgi network. Altogether, we demonstrate that stimulation of this novel calcineurin-Pep4 axis reduces αSyn cytotoxicity.
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http://dx.doi.org/10.3389/fnmol.2017.00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491553PMC
June 2017

The neuroprotective steroid progesterone promotes mitochondrial uncoupling, reduces cytosolic calcium and augments stress resistance in yeast cells.

Microb Cell 2017 May 31;4(6):191-199. Epub 2017 May 31.

Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria.

The steroid hormone progesterone is not only a crucial sex hormone, but also serves as a neurosteroid, thus playing an important role in brain function. Epidemiological data suggest that progesterone improves the recovery of patients after traumatic brain injury. Brain injuries are often connected to elevated calcium spikes, reactive oxygen species (ROS) and programmed cell death affecting neurons. Here, we establish a yeast model to study progesterone-mediated cytoprotection. External supply of progesterone protected yeast cells from apoptosis-inducing stress stimuli and resulted in elevated mitochondrial oxygen uptake accompanied by a drop in ROS generation and ATP levels during chronological aging. In addition, cellular Ca concentrations were reduced upon progesterone treatment, and this effect occurred independently of known Ca transporters and mitochondrial respiration. All effects were also independent of Dap1, the yeast orthologue of the progesterone receptor. Altogether, our observations provide new insights into the cytoprotective effects of progesterone.
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http://dx.doi.org/10.15698/mic2017.06.577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473691PMC
May 2017
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