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  • 1. Aufschnaiter, Andreas
    et al.
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    The vacuolar shapes of ageing: From function to morphology2019In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1866, no 5, p. 957-970Article, review/survey (Refereed)
    Abstract [en]

    Cellular ageing results in accumulating damage to various macromolecules and the progressive decline of organelle function. Yeast vacuoles as well as their counterpart in higher eukaryotes, the lysosomes, emerge as central organelles in lifespan determination. These acidic organelles integrate enzymatic breakdown and recycling of cellular waste with nutrient sensing, storage, signalling and mobilization. Establishing physical contact with virtually all other organelles, vacuoles serve as hubs of cellular homeostasis. Studies in Saccharomyces cerevisiae contributed substantially to our understanding of the ageing process per se and the multifaceted roles of vacuoles/lysosomes in the maintenance of cellular fitness with progressing age. Here, we discuss the multiple roles of the vacuole during ageing, ranging from vacuolar dynamics and acidification as determinants of lifespan to the function of this organelle as waste bin, recycling facility, nutrient reservoir and integrator of nutrient signalling.

  • 2. Aufschnaiter, Andreas
    et al.
    Habernig, Lukas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Kohler, Verena
    Diessl, Jutta
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Carmona-Gutierrez, Didac
    Eisenberg, Tobias
    Keller, Walter
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    The Coordinated Action of Calcineurin and Cathepsin D Protects Against alpha-Synuclein Toxicity2017In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, article id 207Article in journal (Refereed)
    Abstract [en]

    The degeneration of dopaminergic neurons during Parkinson's disease (PD) is intimately linked to malfunction of alpha-synuclein (alpha Syn), the main component of the proteinaceous intracellular inclusions characteristic for this pathology. The cytotoxicity of alpha Syn has been attributed to disturbances in several biological processes conserved from yeast to humans, including Ca2+ 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 Ca2+/calmodulin-dependent phosphatase calcineurin. In a yeast model for PD, high levels of human alpha Syn 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 alpha Syn 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 alpha Syn cytotoxicity.

  • 3. Aufschnaiter, Andreas
    et al.
    Kohler, Verena
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Taking out the garbage: cathepsin D and calcineurin in neurodegeneration2017In: Neural Regeneration Research, ISSN 1673-5374, E-ISSN 1876-7958, Vol. 12, no 11, p. 1776-1779Article, review/survey (Refereed)
    Abstract [en]

    Cellular homeostasis requires a tightly controlled balance between protein synthesis, folding and degradation. Especially long-lived, post-mitotic cells such as neurons depend on an efficient proteostasis system to maintain cellular health over decades. Thus, a functional decline of processes contributing to protein degradation such as autophagy and general lysosomal proteolytic capacity is connected to several age-associated neurodegenerative disorders, including Parkinson's, Alzheimer's and Huntington's diseases. These so called proteinopathies are characterized by the accumulation and misfolding of distinct proteins, subsequently driving cellular demise. We recently linked efficient lysosomal protein breakdown via the protease cathepsin D to the Ca2+/calmodulin-dependent phosphatase calcineurin. In a yeast model for Parkinson's disease, functional calcineurin was required for proper trafficking of cathepsin D to the lysosome and for recycling of its endosomal sorting receptor to allow further rounds of shuttling. Here, we discuss these findings in relation to present knowledge about the involvement of cathepsin D in proteinopathies in general and a possible connection between this protease, calcineurin signalling and endosomal sorting in particular. As dysregulation of Ca2+ homeostasis as well as lysosomal impairment is connected to a plethora of neurodegenerative disorders, this novel interplay might very well impact pathologies beyond Parkinson's disease.

  • 4. Aufschnaiter, Andreas
    et al.
    Kohler, Verena
    Diessl, Jutta
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Peselj, Carlotta
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Carmona-Gutierrez, Didac
    Keller, Walter
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Mitochondrial lipids in neurodegeneration2017In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 367, no 1, p. 125-140Article, review/survey (Refereed)
    Abstract [en]

    Mitochondrial dysfunction is a common feature of many neurodegenerative diseases, including proteinopathies such as Alzheimer's or Parkinson's disease, which are characterized by the deposition of aggregated proteins in the form of insoluble fibrils or plaques. The distinct molecular processes that eventually result in mitochondrial dysfunction during neurodegeneration are well studied but still not fully understood. However, defects in mitochondrial fission and fusion, mitophagy, oxidative phosphorylation and mitochondrial bioenergetics have been linked to cellular demise. These processes are influenced by the lipid environment within mitochondrial membranes as, besides membrane structure and curvature, recruitment and activity of different proteins also largely depend on the respective lipid composition. Hence, the interaction of neurotoxic proteins with certain lipids and the modification of lipid composition in different cell compartments, in particular mitochondria, decisively impact cell death associated with neurodegeneration. Here, we discuss the relevance of mitochondrial lipids in the pathological alterations that result in neuronal demise, focussing on proteinopathies.

  • 5. Aufschnaiter, Andreas
    et al.
    Kohler, Verena
    Walter, Corvin
    Tosal-Castano, Sergi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Habernig, Lukas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wolinski, Heimo
    Keller, Walter
    Vögtle, F-Nora
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    The Enzymatic Core of the Parkinson's Disease-Associated Protein LRRK2 Impairs Mitochondria Biogenesis in Aging Yeast2018In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 11, article id 205Article in journal (Refereed)
    Abstract [en]

    Mitochondrial dysfunction is a prominent trait of cellular decline during aging and intimately linked to neuronal degeneration during Parkinson's disease (PD). Various proteins associated with PD have been shown to differentially impact mitochondrial dynamics, quality control and function, including the leucine-rich repeat kinase 2 (LRRK2). Here, we demonstrate that high levels of the enzymatic core of human LRRK2, harboring GTPase as well as kinase activity, decreases mitochondrial mass via an impairment of mitochondria! biogenesis in aging yeast. We link mitochondrial depletion to a global downregulation of mitochondria-related gene transcripts and show that this catalytic core of LRRK2 localizes to mitochondria and selectively compromises respiratory chain complex IV formation. With progressing cellular age, this culminates in dissipation of mitochondrial transmembrane potential, decreased respiratory capacity, ATP depletion and generation of reactive oxygen species. Ultimately, the collapse of the mitochondrial network results in cell death. A point mutation in LRRK2 that increases the intrinsic GTPase activity diminishes mitochondrial impairment and consequently provides cytoprotection. In sum, we report that a downregulation of mitochondrial biogenesis rather than excessive degradation of mitochondria underlies the reduction of mitochondrial abundance induced by the enzymatic core of LRRK2 in aging yeast cells. Thus, our data provide a novel perspective for deciphering the causative mechanisms of LRRK2-associated PD pathology.

  • 6. Carmona-Gutierrez, Didac
    et al.
    Bauer, Maria Anna
    Zimmermann, Andreas
    Aguilera, Andres
    Austriaco, Nicanor
    Ayscough, Kathryn
    Balzan, Rena
    Bar-Nun, Shoshana
    Barrientos, Antonio
    Belenky, Peter
    Blondel, Marc
    Braun, Ralf J.
    Breitenbach, Michael
    Burhans, William C.
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Cavalieri, Duccio
    Chang, Michael
    Cooper, Katrina F.
    Corte-Real, Manuela
    Costa, Vitor
    Cullin, Christophe
    Dawes, Ian
    Dengjel, Jorn
    Dickman, Martin B.
    Eisenberg, Tobias
    Fahrenkrog, Birthe
    Fasel, Nicolas
    Frohlich, Kai-Uwe
    Gargouri, Ali
    Giannattasio, Sergio
    Goffrini, Paola
    Gourlay, Campbell W.
    Grant, Chris M.
    Greenwood, Michael T.
    Guaragnella, Nicoletta
    Heger, Thomas
    Heinisch, Juergen
    Herker, Eva
    Herrmann, Johannes M.
    Hofer, Sebastian
    Jimenez-Ruiz, Antonio
    Jungwirth, Helmut
    Kainz, Katharina
    Kontoyiannis, Dimitrios P.
    Ludovico, Paula
    Manon, Stephen
    Martegani, Enzo
    Mazzoni, Cristina
    Megeney, Lynn A.
    Meisinger, Chris
    Nielsen, Jens
    Nystrom, Thomas
    Osiewacz, Heinz D.
    Outeiro, Tiago F.
    Park, Hay-Oak
    Pendl, Tobias
    Petranovic, Dina
    Picot, Stephane
    Polcic, Peter
    Powers, Ted
    Ramsdale, Mark
    Rinnerthaler, Mark
    Rockenfeller, Patrick
    Ruckenstuhl, Christoph
    Schaffrath, Raffael
    Segovia, Maria
    Severin, Fedor F.
    Sharon, Amir
    Sigrist, Stephan J.
    Sommer-Ruck, Cornelia
    Sousa, Maria Joao
    Thevelein, Johan M.
    Thevissen, Karin
    Titorenko, Vladimir
    Toledano, Michel B.
    Tuite, Mick
    Voegtle, F. -Nora
    Westermann, Benedikt
    Winderickx, Joris
    Wissing, Silke
    Woelfl, Stefan
    Zhang, Zhaojie J.
    Zhao, Richard Y.
    Zhou, Bing
    Galluzzi, Lorenzo
    Kroemer, Guido
    Madeo, Frank
    Guidelines and recommendations on yeast cell death nomenclature2018In: Microbial cell, E-ISSN 2311-2638, Vol. 5, no 1, p. 4-31Article, review/survey (Refereed)
    Abstract [en]

    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 cellular 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 definition 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 differential definition of terms including apoptosis, regulated necrosis, and autophagic cell death, as we refer to additional cell death routines 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 authors, 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 progress of this vibrant field of research.

  • 7. Eisenberg, Tobias
    et al.
    Abdellatif, Mahmoud
    Schroeder, Sabrina
    Primessnig, Uwe
    Stekovic, Slaven
    Pendl, Tobias
    Harger, Alexandra
    Schipke, Julia
    Zimmermann, Andreas
    Schmidt, Albrecht
    Tong, Mingming
    Ruckenstuhl, Christoph
    Dammbrueck, Christopher
    Gross, Angelina S.
    Herbst, Viktoria
    Magnes, Christoph
    Trausinger, Gert
    Narath, Sophie
    Meinitzer, Andreas
    Hu, Zehan
    Kirsch, Alexander
    Eller, Kathrin
    Carmona-Gutierrez, Didac
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Pietrocola, Federico
    Knittelfelder, Oskar
    Schrepfer, Emilie
    Rockenfeller, Patrick
    Simonini, Corinna
    Rahn, Alexandros
    Horsch, Marion
    Moreth, Kristin
    Beckers, Johannes
    Fuchs, Helmut
    Gailus-Durner, Valerie
    Neff, Frauke
    Janik, Dirk
    Rathkolb, Birgit
    Rozman, Jan
    de Angelis, Martin Hrabe
    Moustafa, Tarek
    Haemmerle, Guenter
    Mayr, Manuel
    Willeit, Peter
    von Frieling-Salewsky, Marion
    Pieske, Burkert
    Scorrano, Luca
    Pieber, Thomas
    Pechlaner, Raimund
    Willeit, Johann
    Sigrist, Stephan J.
    Linke, Wolfgang A.
    Muehlfeld, Christian
    Sadoshima, Junichi
    Dengjel, Joern
    Kiechl, Stefan
    Kroemer, Guido
    Sedej, Simon
    Madeo, Frank
    Cardioprotection and lifespan extension by the natural polyamine spermidine2016In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 22, no 12, p. 1428-1438Article in journal (Refereed)
    Abstract [en]

    Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.

  • 8. Gross, Angelina S.
    et al.
    Zimmermann, Andreas
    Pendl, Tobias
    Schroeder, Sabrina
    Schoenlechner, Hannes
    Knittelfelder, Oskar
    Lamplmayr, Laura
    Santiso, Ana
    Aufschnaiter, Andreas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Waltenstorfer, Daniel
    Ortonobes Lara, Sandra
    Stryeck, Sarah
    Kast, Christina
    Ruckenstuhl, Christoph
    Hofer, Sebastian J.
    Michelitsch, Birgit
    Woelflingseder, Martina
    Müller, Rolf
    Carmona-Gutierrez, Didac
    Madl, Tobias
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Fröhlich, Kai-Uwe
    Shevchenko, Andrej
    Eisenberg, Tobias
    Acetyl-CoA carboxylase 1-dependent lipogenesis promotes autophagy downstream of AMPK2019In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 294, no 32, p. 12020-12039Article in journal (Refereed)
    Abstract [en]

    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 de novo synthesis of lipids. However, it is unclear how de novo 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 (acc1(S/A)) 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, acc1(S/A) 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 acc1(S/A). 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.

  • 9.
    Kaimal, Jayasankar Mohanakrishnan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Habernig, Lukas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Andréasson, Claes
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nuclear targeting of Hsp110 modifies the proteostasis system by mobilizing latent Hsp70 chaperonesManuscript (preprint) (Other academic)
  • 10. Kohler, Verena
    et al.
    Goessweiner-Mohr, Nikolaus
    Aufschnaiter, Andreas
    Fercher, Christian
    Probst, Ines
    Pavkov-Keller, Tea
    Hunger, Kristin
    Wolinski, Heimo
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Grohmann, Elisabeth
    Keller, Walter
    TraN: A novel repressor of an Enterococcus conjugative type IV secretion system2018In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 17, p. 9201-9219Article in journal (Refereed)
    Abstract [en]

    The dissemination of multi-resistant bacteria represents an enormous burden on modern healthcare. Plasmid-borne conjugative transfer is the most prevalent mechanism, requiring a type IV secretion system that enables bacteria to spread beneficial traits, such as resistance to last-line antibiotics, among different genera. Inc18 plasmids, like the Gram-positive broad host-range plasmid pIP501, are substantially involved in propagation of vancomycin resistance from Enterococci to methicillin-resistant strains of Staphylococcus aureus. Here, we identified the small cytosolic protein TraN as a repressor of the pIP501-encoded conjugative transfer system, since deletion of traN resulted in upregulation of transfer factors, leading to highly enhanced conjugative transfer. Furthermore, we report the complex structure of TraN with DNA and define the exact sequence of its binding motif. Targeting this protein-DNA interaction might represent a novel therapeutic approach against the spreading of antibiotic resistances.

  • 11. Kohler, Verena
    et al.
    Probst, Ines
    Aufschnaiter, Andreas
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Schaden, Lisa
    Rechberger, Gerald N.
    Koraimann, Günther
    Grohmann, Elisabeth
    Keller, Walter
    Conjugative type IV secretion in Gram-positive pathogens: TraG, a lytic transglycosylase and endopeptidase, interacts with translocation channel protein TraM2017In: Plasmid, ISSN 0147-619X, E-ISSN 1095-9890, Vol. 91, p. 9-18Article in journal (Refereed)
    Abstract [en]

    Conjugative transfer plays a major role in the transmission of antibiotic resistance in bacteria. pIP501 is a Grampositive conjugative model plasmid with the broadest transfer host-range known so far and is frequently found in Enterococcus faecalis and Enterococcus faecium clinical isolates. The pIP501 type IV secretion system is encoded by 15 transfer genes. In this work, we focus on the VirB1-like protein TraG, a modular peptidoglycan metabolizing enzyme, and the VirB8-homolog TraM, a potential member of the translocation channel. By providing full-length traG in trans, but not with a truncated variant, we achieved full recovery of wild type transfer efficiency in the traG-knockout mutant E. faecalis pIP501AtraG. With peptidoglycan digestion experiments and tandem mass spectrometry we could assign lytic transglycosylase and endopeptidase activity to TraG, with the CHAP domain alone displaying endopeptidase activity. We identified a novel interaction between TraG and TraM in a bacterial 2-hybrid assay. In addition we found that both proteins localize in focal spots at the E. faecalis cell membrane using immunostaining and fluorescence microscopy. Extracellular protease digestion to evaluate protein cell surface exposure revealed that correct membrane localization of TraM requires the transmembrane helix of TraG. Thus, we suggest an essential role for TraG in the assembly of the pIP501 type IV secretion system.

  • 12. Leibiger, Christine
    et al.
    Deisel, Jana
    Aufschnaiter, Andreas
    Ambros, Stefanie
    Tereshchenko, Maria
    Verheijen, Bert M.
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Braun, Ralf J.
    TDP-43 controls lysosomal pathways thereby determining its own clearance and cytotoxicity2018In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 9, p. 1593-1607Article in journal (Refereed)
    Abstract [en]

    TDP-43 is a nuclear RNA-binding protein whose cytoplasmic accumulation is the pathological hallmark of amyotrophic lateral sclerosis (ALS). For a better understanding of this devastating disorder at the molecular level, it is important to identify cellular pathways involved in the clearance of detrimental TDP-43. Using a yeast model system, we systematically analyzed to which extent TDP-43-triggered cytotoxicity is modulated by conserved lysosomal clearance pathways. We observed that the lysosomal fusion machinery and the endolysosomal pathway, which are crucial for proper lysosomal function, were pivotal for survival of cells exposed to TDP-43. Interestingly, TDP-43 itself interfered with these critical TDP-43 clearance pathways. In contrast, autophagy played a complex role in this process. It contributed to the degradation of TDP-43 in the absence of endolysosomal pathway activity, but its induction also enhanced cell death. Thus, TDP-43 interfered with lysosomal function and its own degradation via lysosomal pathways, and triggered lethal autophagy. We propose that these effects critically contribute to cellular dysfunction in TDP-43 proteinopathies.

  • 13. Ring, Julia
    et al.
    Rockenfeller, Patrick
    Abraham, Claudia
    Tadic, Jelena
    Poglitsch, Michael
    Schimmel, Katherina
    Westermayer, Julia
    Schauer, Simon
    Achleitner, Bettina
    Schimpel, Christa
    Moitzi, Barbara
    Rechberger, Gerald N.
    Sigrist, Stephan J.
    Carmona-Gutierrez, Didac
    Kroemer, Guido
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Eisenberg, Tobias
    Madeo, Frank
    Mitochondrial energy metabolism is required for lifespan extension by the spastic paraplegia-associated protein spartin2017In: Microbial Cell, ISSN 2311-2638, Vol. 4, no 12, p. 411-422Article in journal (Refereed)
    Abstract [en]

    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 Drosophila 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-fructokinase-2,6 (Pfk26) and is sufficient to complement for PFK26-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.

  • 14. Rockenfeller, Patrick
    et al.
    Smolnig, Martin
    Diessl, Jutta
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. NAWI Graz, Austria; University of Graz, Austria.
    Bashir, Mina
    Schmiedhofer, Vera
    Knittelfelder, Oskar
    Ring, Julia
    Franz, Joakim
    Foessl, Ines
    Khan, Muhammad J.
    Rost, René
    Graier, Wolfgang F.
    Kroemer, Guido
    Zimmermann, Andreas
    Carmona-Gutierrez, Didac
    Eisenberg, Tobias
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. NAWI Graz, Austria; University of Graz, Austria.
    Sigrist, Stephan J.
    Kühnlein, Ronald P.
    Kohlwein, Sepp D.
    Gourlay, Campbell W.
    Madeo, Frank
    Diacylglycerol triggers Rim101 pathway-dependent necrosis in yeast: a model for lipotoxicity2018In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 25, no 4, p. 765-781Article in journal (Refereed)
    Abstract [en]

    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-dioctanoyls-n-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.

  • 15.
    Suhm, Tamara
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Habernig, Lukas
    Rzepka, Magdalena
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kaimal, Jayasankar Mohanakrishnan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Andréasson, Claes
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Ott, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    A novel system to monitor mitochondrial translation in yeast2018In: Microbial Cell, ISSN 2311-2638, Vol. 5, no 3, p. 158-164Article in journal (Refereed)
    Abstract [en]

    The mitochondrial genome is responsible for the production of a handful of polypeptides that are core subunits of the membrane-bound oxidative phosphorylation system. Until now the mechanistic studies of mitochondrial protein synthesis inside cells have been conducted with inhibition of cytoplasmic protein synthesis to reduce the background of nuclear gene expression with the undesired consequence of major disturbances of cellular signaling cascades. Here we have generated a system that allows direct monitoring of mitochondrial translation in unperturbed cells. A recoded gene for superfolder GFP was inserted into the yeast (Saccharomyces cerevisiae) mitochondrial genome and enabled the detection of translation through fluorescence microscopy and flow cytometry in functional mitochondria. This novel tool allows the investigation of the function and regulation of mitochondrial translation during stress signaling, aging and mitochondrial biogenesis.

  • 16.
    Suhm, Tamara
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kaimal, Jayasankar Mohanakrishnan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Dawitz, Hannah
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Peselj, Carlotta
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Masser, Anna E.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hanzén, Sarah
    Ambrožič, Matevž
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Smialowska, Agata
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Björck, Markus L.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Brzezinski, Peter
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Nyström, Thomas
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Andréasson, Claes
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ott, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mitochondrial Translation Efficiency Controls Cytoplasmic Protein Homeostasis2018In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 27, no 6, p. 1309-1322Article in journal (Refereed)
    Abstract [en]

    Cellular proteostasis ismaintained via the coordinated synthesis, maintenance, and breakdown of proteins in the cytosol and organelles. While biogenesis of the mitochondrial membrane complexes that execute oxidative phosphorylation depends on cytoplasmic translation, it is unknown how translation within mitochondria impacts cytoplasmic proteostasis and nuclear gene expression. Here we have analyzed the effects of mutations in the highly conserved accuracy center of the yeast mitoribosome. Decreased accuracy of mitochondrial translation shortened chronological lifespan, impaired management of cytosolic protein aggregates, and elicited a general transcriptional stress response. In striking contrast, increased accuracy extended lifespan, improved cytosolic aggregate clearance, and suppressed a normally stress-induced, Msn2/4-dependent interor-ganellar proteostasis transcription program (IPTP) that regulates genes important for mitochondrial proteostasis. Collectively, the data demonstrate that cytosolic protein homeostasis and nuclear stress signaling are controlled by mitochondrial translation efficiency in an inter-connected organelle quality control network that determines cellular lifespan.

  • 17. Yeaman, Michael R.
    et al.
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Thevissen, Karin
    Regulated Cell Death as a Therapeutic Target for Novel Antifungal Peptides and Biologics2018In: Oxidative Medicine and Cellular Longevity, ISSN 1942-0900, E-ISSN 1942-0994, Vol. 2018, article id 5473817Article, review/survey (Refereed)
    Abstract [en]

    The rise of microbial pathogens refractory to conventional antibiotics represents one of the most urgent and global public health concerns for the 21st century. Emergence of Candida auris isolates and the persistence of invasive mold infections that resist existing treatment and cause severe illness has underscored the threat of drug-resistant fungal infections. To meet these growing challenges, mechanistically novel agents and strategies are needed that surpass the conventional fungistatic or fungicidal drug actions. Host defense peptides have long been misunderstood as indiscriminant membrane detergents. However, evidence gathered over the past decade clearly points to their sophisticated and selective mechanisms of action, including exploiting regulated cell death pathways of their target pathogens. Such peptides perturb transmembrane potential and mitochondrial energetics, inducing phosphatidylserine accessibility and metacaspase activation in fungi. These mechanisms are often multimodal, affording target pathogens fewer resistance options as compared to traditional small molecule drugs. Here, recent advances in the field are examined regarding regulated cell death subroutines as potential therapeutic targets for innovative anti-infective peptides against pathogenic fungi. Furthering knowledge of protective host defense peptide interactions with target pathogens is key to advancing and applying novel prophylactic and therapeutic countermeasures to fungal resistance and pathogenesis.

1 - 17 of 17
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