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  • 1.
    Berndtsson, Jens
    et al.
    Department of Biochemistry and Biophysics Stockholm University Stockholm Sweden.
    Kohler, Andreas
    Department of Biochemistry and Biophysics Stockholm University Stockholm Sweden.
    Rathore, Sorbhi
    Department of Biochemistry and Biophysics Stockholm University Stockholm Sweden.
    Marin‐Buera, Lorena
    Department of Biochemistry and Biophysics Stockholm University Stockholm Sweden.
    Dawitz, Hannah
    Department of Biochemistry and Biophysics Stockholm University Stockholm Sweden.
    Diessl, Jutta
    Department of Molecular Biosciences The Wenner‐Gren Institute Stockholm University Stockholm Sweden.
    Kohler, Verena
    Department of Molecular Biosciences The Wenner‐Gren Institute Stockholm University Stockholm Sweden.
    Barrientos, Antoni
    Department of Neurology Miller School of Medicine University of Miami Miami FL USA;Department of Biochemistry and Molecular Biology Miller School of Medicine University of Miami Miami FL USA.
    Büttner, Sabrina
    Department of Molecular Biosciences The Wenner‐Gren Institute Stockholm University Stockholm Sweden;Institute of Molecular Biosciences University of Graz Graz Austria.
    Fontanesi, Flavia
    Department of Biochemistry and Molecular Biology Miller School of Medicine University of Miami Miami FL USA.
    Ott, Martin
    Department of Biochemistry and Biophysics Stockholm University Stockholm Sweden;Department of Medical Biochemistry and Cell Biology University of Gothenburg Gothenburg Sweden.
    Respiratory supercomplexes enhance electron transport by decreasing cytochrome c diffusion distance2020In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 21, no 12, article id e51015Article in journal (Refereed)
    Abstract [en]

    Respiratory chains are crucial for cellular energy conversion and consist of multi-subunit complexes that can assemble into supercomplexes. These structures have been intensively characterized in various organisms, but their physiological roles remain unclear. Here, we elucidate their function by leveraging a high-resolution structural model of yeast respiratory supercomplexes that allowed us to inhibit supercomplex formation by mutation of key residues in the interaction interface. Analyses of a mutant defective in supercomplex formation, which still contains fully functional individual complexes, show that the lack of supercomplex assembly delays the diffusion of cytochrome c between the separated complexes, thus reducing electron transfer efficiency. Consequently, competitive cellular fitness is severely reduced in the absence of supercomplex formation and can be restored by overexpression of cytochrome c. In sum, our results establish how respiratory supercomplexes increase the efficiency of cellular energy conversion, thereby providing an evolutionary advantage for aerobic organisms.

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  • 2.
    Diessl, Jutta
    et al.
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Berndtsson, Jens
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Broeskamp, Filomena
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Habernig, Lukas
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Kohler, Verena
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Vazquez-Calvo, Carmela
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Nandy, Arpita
    Institute of Biochemistry and Molecular Biology, ZBMZ, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany.
    Peselj, Carlotta
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Drobysheva, Sofia
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Pelosi, Ludovic
    Univ. Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, Grenoble, France.
    Vögtle, F.-Nora
    Institute of Biochemistry and Molecular Biology, ZBMZ, University of Freiburg, Freiburg, Germany;CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany; Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany; Network Aging Research, Heidelberg University, Heidelberg, Germany.
    Pierrel, Fabien
    Univ. Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, Grenoble, France.
    Ott, Martin
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Büttner, Sabrina
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Manganese-driven CoQ deficiency2022In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 6061Article in journal (Refereed)
    Abstract [en]

    Overexposure to manganese disrupts cellular energy metabolism across species, but the molecular mechanism underlying manganese toxicity remains enigmatic. Here, we report that excess cellular manganese selectively disrupts coenzyme Q (CoQ) biosynthesis, resulting in failure of mitochondrial bioenergetics. While respiratory chain complexes remain intact, the lack of CoQ as lipophilic electron carrier precludes oxidative phosphorylation and leads to premature cell and organismal death. At a molecular level, manganese overload causes mismetallation and proteolytic degradation of Coq7, a diiron hydroxylase that catalyzes the penultimate step in CoQ biosynthesis. Coq7 overexpression or supplementation with a CoQ headgroup analog that bypasses Coq7 function fully corrects electron transport, thus restoring respiration and viability. We uncover a unique sensitivity of a diiron enzyme to mismetallation and define the molecular mechanism for manganese-induced bioenergetic failure that is conserved across species.

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  • 3.
    Fercher, Christian
    et al.
    Institute of Molecular Biosciences, NAWI Graz, University of Graz, Austria.
    Probst, Ines
    Division of Infectious Diseases, University Medical Center Freiburg, Germany; Faculty of Biology, Microbiology, Albert-Ludwigs-University Freiburg, Germany.
    Kohler, Verena
    Institute of Molecular Biosciences, NAWI Graz, University of Graz, Austria.
    Goessweiner-Mohr, Nikolaus
    Center for Structural System Biology (CSSB), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany; Deutsches Elektronen-Synchrotron (DESY), Hamburg, Germany; Institute of Molecular Biotechnology (IMBA), Austrian Academy of Sciences, Vienna, Austria; Research Institute of Molecular Pathology (IMP), Vienna, Austria.
    Arends, Karsten
    Robert Koch Institute, Berlin, Germany.
    Grohmann, Elisabeth
    Division of Infectious Diseases, University Medical Center Freiburg, Germany; Beuth University of Applied Sciences, Berlin, Germany.
    Zangger, Klaus
    Institute of Chemistry, University of Graz, Graz, Austria.
    Meyer, N. Helge
    Department of General and Visceral Surgery, University of Oldenburg, Germany.
    Keller, Walter
    Institute of Molecular Biosciences, NAWI Graz, University of Graz, Austria.
    VirB8-like protein TraH is crucial for DNA transfer in Enterococcus faecalis2016In: Scientific Reports, E-ISSN 2045-2322, Vol. 6, no 1, article id 24643Article in journal (Refereed)
    Abstract [en]

    Untreatable bacterial infections caused by a perpetual increase of antibiotic resistant strains represent a serious threat to human healthcare in the 21st century. Conjugative DNA transfer is the most important mechanism for antibiotic resistance and virulence gene dissemination among bacteria and is mediated by a protein complex, known as type IV secretion system (T4SS). The core of the T4SS is a multiprotein complex that spans the bacterial envelope as a channel for macromolecular secretion. We report the NMR structure and functional characterization of the transfer protein TraH encoded by the conjugative Gram-positive broad-host range plasmid pIP501. The structure exhibits a striking similarity to VirB8 proteins of Gram-negative secretion systems where they play an essential role in the scaffold of the secretion machinery. Considering TraM as the first VirB8-like protein discovered in pIP501, TraH represents the second protein affiliated with this family in the respective transfer operon. A markerless traH deletion in pIP501 resulted in a total loss of transfer in Enterococcus faecalis as compared with the pIP501 wild type (wt) plasmid, demonstrating that TraH is essential for pIP501 mediated conjugation. Moreover, oligomerization state and topology of TraH in the native membrane were determined providing insights in molecular organization of a Gram-positive T4SS.

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  • 4.
    Grohmann, Elisabeth
    et al.
    Life Sciences and Technology, Beuth University of Applied Sciences Berlin, Berlin, Germany.
    Kohler, Verena
    Institute of Molecular Biosciences, University of Graz, Graz, Austria; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Vaishampayan, Ankita
    Life Sciences and Technology, Beuth University of Applied Sciences Berlin, Berlin, Germany.
    Acquired resistance from gene transfer2019In: Antibiotic drug resistance / [ed] José-Luis Capelo-Martínez; Gilberto Igrejas, John Wiley & Sons, 2019, p. 141-165Chapter in book (Refereed)
    Abstract [en]

    The occurrence of multiple antibiotic-resistant pathogens is steadily increasing, and their presence is not limited to clinical settings as they are also encountered in the environment. Horizontal gene transfer is a crucial means of generation and spread of multiresistant pathogenic bacteria. It is subdivided into three different mechanisms: conjugation (conjugative transfer), transformation, and transduction, of which conjugative transfer of plasmids and integrative conjugative elements (ICE) is the most important one. In 2017, the World Health Organization (WHO) published a list of antibiotic-resistant bacterial pathogens for which alternative drugs or treatments need to be urgently developed. Here, we review the spread and transfer mechanisms of these antibiotic resistances and end with current approaches, which could aid in tackling them.

  • 5.
    Keuenhof, Katharina S.
    et al.
    Department for Chemistry and Molecular biology, University of Gothenburg, Sweden.
    Kohler, Verena
    Institute of Molecular Biosciences, University of Graz, Austria; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Sweden.
    Broeskamp, Filomena
    Department for Chemistry and Molecular biology, University of Gothenburg, Sweden.
    Panagaki, Dimitra
    Department for Chemistry and Molecular biology, University of Gothenburg, Sweden.
    Speese, Sean D.
    Knight Cancer Early Detection Advanced Research Center, Oregon Health and Science University, 2720 S Moody Ave, Portland, OR, 97201, USA.
    Büttner, Sabrina
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Sweden.
    Höög, Johanna L.
    Department for Chemistry and Molecular biology, University of Gothenburg, Sweden.
    Nuclear envelope budding and its cellular functions2023In: Nucleus, ISSN 1949-1034, E-ISSN 1949-1042, Vol. 14, no 1, article id 2178184Article in journal (Refereed)
    Abstract [en]

    The nuclear pore complex (NPC) has long been assumed to be the sole route across the nuclear envelope, and under normal homeostatic conditions it is indeed the main mechanism of nucleo-cytoplasmic transport. However, it has also been known that e.g. herpesviruses cross the nuclear envelope utilizing a pathway entitled nuclear egress or envelopment/de-envelopment. Despite this, a thread of observations suggests that mechanisms similar to viral egress may be transiently used also in healthy cells. It has since been proposed that mechanisms like nuclear envelope budding (NEB) can facilitate the transport of RNA granules, aggregated proteins, inner nuclear membrane proteins, and mis-assembled NPCs. Herein, we will summarize the known roles of NEB as a physiological and intrinsic cellular feature and highlight the many unanswered questions surrounding these intriguing nuclear events.

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  • 6. Kohler, Andreas
    et al.
    Carlström, Andreas
    Nolte, Hendrik
    Kohler, Verena
    Jung, Sung-jun
    Sridhara, Sagar
    Tatsuta, Takashi
    Berndtsson, Jens
    Langer, Thomas
    Ott, Martin
    Early fate decision for mitochondrially encoded proteins by a molecular triage2023In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 83, no 19, p. 3470-3484Article in journal (Refereed)
    Abstract [en]

    Folding of newly synthesized proteins poses challenges for a functional proteome. Dedicated protein quality control (PQC) systems either promote the folding of nascent polypeptides at ribosomes or, if this fails, ensure their degradation. Although well studied for cytosolic protein biogenesis, it is not understood how these processes work for mitochondrially encoded proteins, key subunits of the oxidative phosphorylation (OXPHOS) system. Here, we identify dedicated hubs in proximity to mitoribosomal tunnel exits coordinating mitochondrial protein biogenesis and quality control. Conserved prohibitin (PHB)/m-AAA protease supercomplexes and the availability of assembly chaperones determine the fate of newly synthesized proteins by molecular triaging. The localization of these competing activities in the vicinity of the mitoribosomal tunnel exit allows for a prompt decision on whether newly synthesized proteins are fed into OXPHOS assembly or are degraded.

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  • 7. Kohler, Andreas
    et al.
    Habernig, Lukas
    Kohler, Verena
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Diessl, Jutta
    Carmona-Gutierrez, Didac
    Eisenberg, Tobias
    Keller, Walter
    Büttner, Sabrina
    The coordinated action of calcineurin and cathepsin d protects against α-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 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 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 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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  • 8. Kohler, Andreas
    et al.
    Kohler, Verena
    Institute of Molecular Biosciences, University of Graz, Austria.
    Büttner, Sabrina
    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. 1776-1776Article in journal (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.

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  • 9. Kohler, Andreas
    et al.
    Kohler, Verena
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Büttner, Sabrina
    The mitochondrial network in Parkinson's disease2020In: Genetics, neurology, behavior, and diet in parkinson's disease: The neuroscience of parkinson's, volume 2, Academic Press, 2020, p. 123-138Chapter in book (Refereed)
    Abstract [en]

    Neuronal dysfunction during sporadic and familial forms of Parkinson’s disease is intimately connected to mitochondrial dysfunction. Diverse genetic and environmental factors contributing to Parkinson’s disease development and progression have been shown to interfere with and to compromise mitochondrial bioenergetics, dynamics and trafficking. Mitochondria are highly dynamic organelles, constantly changing shape and abundance via coordinated fission and fusion events to adapt to cellular needs. Moreover, direct contact between mitochondria and other organelles allows interconnected signaling, and exchange of metabolites and ions. Several proteins associated with familial Parkinson’s disease modulate the equilibrium between fission and fusion, govern distinct mitochondrial degradation pathways and impact the formation of tethering complexes that facilitate interorganellar contact. Here, we discuss molecular mechanisms of mitochondrial dysfunction in Parkinson’s disease, focusing on mitochondrial dynamics and contact sites. 

  • 10.
    Kohler, Andreas
    et al.
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Kohler, Verena
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Diessl, Jutta
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Peselj, Carlotta
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Carmona-Gutierrez, Didac
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Keller, Walter
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Büttner, Sabrina
    Institute of Molecular Biosciences, University of Graz, Graz, Austria; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Mitochondrial lipids in neurodegeneration2016In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 367, no 1, p. 125-140Article in journal (Other academic)
    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.

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  • 11. Kohler, Andreas
    et al.
    Kohler, Verena
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Khalifa, Shaden
    Abd El-Wahed, Aida
    Du, Ming
    El-Seedi, Hesham
    Büttner, Sabrina
    Apitoxin and its components against cancer, neurodegeneration and rheumatoid arthritis: limitations and possibilities2020In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 12, no 2, article id 66Article in journal (Refereed)
    Abstract [en]

    Natural products represent important sources for the discovery and design of novel drugs. Bee venom and its isolated components have been intensively studied with respect to their potential to counteract or ameliorate diverse human diseases. Despite extensive research and significant advances in recent years, multifactorial diseases such as cancer, rheumatoid arthritis and neurodegenerative diseases remain major healthcare issues at present. Although pure bee venom, apitoxin, is mostly described to mediate anti-inflammatory, anti-arthritic and neuroprotective effects, its primary component melittin may represent an anticancer therapeutic. In this review, we approach the possibilities and limitations of apitoxin and its components in the treatment of these multifactorial diseases. We further discuss the observed unspecific cytotoxicity of melittin that strongly restricts its therapeutic use and review interesting possibilities of a beneficial use by selectively targeting melittin to cancer cells.

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  • 12.
    Kohler, Andreas
    et al.
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Kohler, Verena
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Walter, Corvin
    Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
    Tosal-Castano, Sergi
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Habernig, Lukas
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Wolinski, Heimo
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Keller, Walter
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Vögtle, F.-Nora
    Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
    Büttner, Sabrina
    Institute of Molecular Biosciences, University of Graz, Graz, Austria; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    The enzymatic core of the Parkinson’s disease-associated protein LRRK2 impairs mitochondrial 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 mitochondrial 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.

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  • 13.
    Kohler, Verena
    et al.
    Department of Molecular Biosciences , The Wenner-Gren Institute, Stockholm University , S-106 91 Stockholm , Sweden.
    Andréasson, Claes
    Department of Molecular Biosciences , The Wenner-Gren Institute, Stockholm University , S-106 91 Stockholm , Sweden.
    Hsp70-mediated quality control: should I stay or should I go?2020In: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 401, no 11, p. 1233-1248Article, review/survey (Refereed)
    Abstract [en]

    Chaperones of the 70 kDa heat shock protein (Hsp70) superfamily are key components of the cellular proteostasis system. Together with its co-chaperones, Hsp70 forms proteostasis subsystems that antagonize protein damage during physiological and stress conditions. This function stems from highly regulated binding and release cycles of protein substrates, which results in a flow of unfolded, partially folded and misfolded species through the Hsp70 subsystem. Specific factors control how Hsp70 makes decisions regarding folding and degradation fates of the substrate proteins. In this review, we summarize how the flow of Hsp70 substrates is controlled in the cell with special emphasis on recent advances regarding substrate release mechanisms.

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  • 14.
    Kohler, Verena
    et al.
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Andréasson, Claes
    Department of Molecular Biosciences, Stockholm University, Stockholm, Sweden.
    Reversible protein assemblies in the proteostasis network in health and disease2023In: Frontiers in Molecular Biosciences, E-ISSN 2296-889X, Vol. 10, article id 1155521Article in journal (Refereed)
    Abstract [en]

    While proteins populating their native conformations constitute the functional entities of cells, protein aggregates are traditionally associated with cellular dysfunction, stress and disease. During recent years, it has become clear that large aggregate-like protein condensates formed via liquid-liquid phase separation age into more solid aggregate-like particles that harbor misfolded proteins and are decorated by protein quality control factors. The constituent proteins of the condensates/aggregates are disentangled by protein disaggregation systems mainly based on Hsp70 and AAA ATPase Hsp100 chaperones prior to their handover to refolding and degradation systems. Here, we discuss the functional roles that condensate formation/aggregation and disaggregation play in protein quality control to maintain proteostasis and why it matters for understanding health and disease.

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  • 15.
    Kohler, Verena
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Arunagiri, Anoop
    Department of Internal Medicine, University of Michigan, MI, Ann Arbor, United States.
    Ventura, Salvador
    Departament de Bioquímica i Biologia Molecular, Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autònoma de Barcelona, Barcelona, Spain.
    Kroschwald, Sonja
    Department of Biology, Institute of Biochemistry, Zürich, Switzerland.
    Ranganathan, Srivastav
    Department of Chemistry and Chemical Biology, Harvard University, MA, Cambridge, United States.
    Editorial: molecular determinants of protein assemblies in health and disease, volume II2023In: Frontiers in Molecular Biosciences, E-ISSN 2296-889X, Vol. 10, article id 1343082Article in journal (Other academic)
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  • 16.
    Kohler, Verena
    et al.
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Braun, Ralf J.
    Research Division for Neurodegenerative Diseases, Center for Biosciences, Department of Medicine, Faculty of Medicine and Dentistry, Danube Private University, Krems an der Donau, Austria.
    Kohler, Andreas
    Institute of Molecular Biosciences, University of Graz, Graz, Austria; Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Editorial: Mitochondria as a hub for neurodegenerative disorders2023In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 16, article id 1147468Article in journal (Other academic)
  • 17.
    Kohler, Verena
    et al.
    Department of Molecular Biosciences, The Wenner‐Gren Institute, Stockholm University, Stockholm, Sweden.
    Büttner, Sabrina
    Department of Molecular Biosciences, The Wenner‐Gren Institute, Stockholm University, Stockholm, Sweden; Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Remodelling of nucleus-vacuole junctions during metabolic and proteostatic stress2021In: Contact, ISSN 2515-2564, Vol. 4Article in journal (Refereed)
    Abstract [en]

    Cellular adaptation to stress and metabolic cues requires a coordinated response of different intracellular compartments, separated by semipermeable membranes. One way to facilitate interorganellar communication is via membrane contact sites, physical bridges between opposing organellar membranes formed by an array of tethering machineries. These contact sites are highly dynamic and establish an interconnected organellar network able to quickly respond to external and internal stress by changing size, abundance and molecular architecture. Here, we discuss recent work on nucleus-vacuole junctions, connecting yeast vacuoles with the nucleus. Appearing as small, single foci in mitotic cells, these contacts expand into one enlarged patch upon nutrient exhaustion and entry into quiescence or can be shaped into multiple large foci essential to sustain viability upon proteostatic stress at the nuclear envelope. We highlight the remarkable plasticity and rapid remodelling of these contact sites upon metabolic or proteostatic stress and their emerging importance for cellular fitness.

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  • 18.
    Kohler, Verena
    et al.
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Goessweiner-Mohr, Nikolaus
    Institute of Molecular Biosciences, University of Graz, Graz, Austria; Institute of Biophysics, Johannes Kepler University, Linz, Austria.
    Kohler, Andreas
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Fercher, Christian
    Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Australia.
    Probst, Ines
    Division of Infectious Diseases, University Medical Center Freiburg, Freiburg, Germany.
    Pavkov-Keller, Tea
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Hunger, Kristin
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Wolinski, Heimo
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Büttner, Sabrina
    Institute of Molecular Biosciences, University of Graz, Graz, Austria; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Grohmann, Elisabeth
    Division of Infectious Diseases, University Medical Center Freiburg, Freiburg, Germany; Life Sciences and Technology, Beuth University of Applied Sciences, Berlin, Germany.
    Keller, Walter
    Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed-Graz, Austria.
    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.

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  • 19.
    Kohler, Verena
    et al.
    Institute of Molecular Biosciences, BioTechMed, University of Graz, Graz, Austria.
    Keller, Walter
    Institute of Molecular Biosciences, BioTechMed, University of Graz, Graz, Austria.
    Grohmann, Elisabeth
    Life Sciences and Technology, Beuth University of Applied Sciences, Berlin, Germany.
    Enterococcus adhesin PrgB facilitates type IV secretion by condensation of extracellular DNA2018In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 109, no 3, p. 263-267Article in journal (Refereed)
    Abstract [en]

    Conjugative type IV secretion systems (T4SSs) are multi-protein complexes in Gram-negative and Gram-positive (G+) bacteria, responsible for spreading antibiotic resistances and virulence factors among different species. Compared to Gram-negative bacteria, which establish close contacts for conjugative transfer via sex pili, G+ T4SSs are suggested to employ surface adhesins instead. One example is pCF10, an enterococcal conjugative sex-pheromone responsive plasmid with a narrow host range, thus disseminating genetic information only among closely related species. This MicroCommentary is dedicated to the crystal structure of the pCF10-encoded adhesion domain of PrgB presented by Schmitt et al. The authors show in their work that this adhesion domain is responsible for biofilm formation, tight binding and condensation of extracellular DNA (eDNA) and conjugative transfer of pCF10. A sophisticated two-step mechanism for highly efficient conjugative transfer is postulated, including the formation of PrgB-mediated long-range intercellular contacts by binding and establishment of shorter-range contacts via condensation of eDNA. PrgB binding to lipoteichoic acid on the recipient cell surface stabilizes junctions between the mating partners. The major findings by Schmitt et al. will be brought into a broader context and potential medical applications targeting eDNA as essential component in biofilm formation and conjugation will be discussed.

  • 20.
    Kohler, Verena
    et al.
    Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria.
    Keller, Walter
    Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria.
    Grohmann, Elisabeth
    Life Sciences and Technology, Beuth University of Applied Sciences Berlin, Berlin, Germany.
    Regulation of gram-positive conjugation2019In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 10, article id 1134Article in journal (Refereed)
    Abstract [en]

    Type IV Secretion Systems (T4SSs) are membrane-spanning multiprotein complexes dedicated to protein secretion or conjugative DNA transport (conjugation systems) in bacteria. The prototype and best-characterized T4SS is that of the Gram-negative soil bacterium Agrobacterium tumefaciens. For Gram-positive bacteria, only conjugative T4SSs have been characterized in some biochemical, structural, and mechanistic details. These conjugation systems are predominantly encoded by self-transmissible plasmids but are also increasingly detected on integrative and conjugative elements (ICEs) and transposons. Here, we report regulatory details of conjugation systems from Enterococcus model plasmids pIP501 and pCF10, Bacillus plasmid pLS1, Clostridium plasmid pCW3, and staphylococcal plasmid pSK41. In addition, regulation of conjugative processes of ICEs (ICEBs1, ICESt1, ICESt3) by master regulators belonging to diverse repressor families will be discussed. A special focus of this review lies on the comparison of regulatory mechanisms executed by proteins belonging to the RRNPP family. These regulators share a common fold and govern several essential bacterial processes, including conjugative transfer.

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  • 21.
    Kohler, Verena
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Kohler, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Institute of Molecular Biosciences, University of Graz, Graz, Austria; Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Berglund, Lisa Larsson
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
    Hao, Xinxin
    Department of Microbiology and Immunology, University of Gothenburg, Gothenburg, Sweden.
    Gersing, Sarah
    The Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
    Imhof, Axel
    Biomedical Center Munich, Faculty of Medicine, Ludwig Maximilian University of Munich, Planegg-Martinsried, Germany.
    Nyström, Thomas
    Department of Microbiology and Immunology, University of Gothenburg, Gothenburg, Sweden.
    Höög, Johanna L.
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
    Ott, Martin
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.
    Andréasson, Claes
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Büttner, Sabrina
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Nuclear Hsp104 safeguards the dormant translation machinery during quiescence2024In: Nature Communications, E-ISSN 2041-1723, Vol. 15, no 1, article id 315Article in journal (Refereed)
    Abstract [en]

    The resilience of cellular proteostasis declines with age, which drives protein aggregation and compromises viability. The nucleus has emerged as a key quality control compartment that handles misfolded proteins produced by the cytosolic protein biosynthesis system. Here, we find that age-associated metabolic cues target the yeast protein disaggregase Hsp104 to the nucleus to maintain a functional nuclear proteome during quiescence. The switch to respiratory metabolism and the accompanying decrease in translation rates direct cytosolic Hsp104 to the nucleus to interact with latent translation initiation factor eIF2 and to suppress protein aggregation. Hindering Hsp104 from entering the nucleus in quiescent cells results in delayed re-entry into the cell cycle due to compromised resumption of protein synthesis. In sum, we report that cytosolic-nuclear partitioning of the Hsp104 disaggregase is a critical mechanism to protect the latent protein synthesis machinery during quiescence in yeast, ensuring the rapid restart of translation once nutrients are replenished.

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  • 22.
    Kohler, Verena
    et al.
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Kohler, Andreas
    Büttner, Sabrina
    Closing the gap: membrane contact sites in the regulation of autophagy2020In: Cells, E-ISSN 2073-4409, Vol. 9, no 5, p. 1184-1184Article, review/survey (Refereed)
    Abstract [en]

    In all eukaryotic cells, intracellular organization and spatial separation of incompatible biochemical processes is established by individual cellular subcompartments in form of membrane-bound organelles. Virtually all of these organelles are physically connected via membrane contact sites (MCS), allowing interorganellar communication and a functional integration of cellular processes. These MCS coordinate the exchange of diverse metabolites and serve as hubs for lipid synthesis and trafficking. While this of course indirectly impacts on a plethora of biological functions, including autophagy, accumulating evidence shows that MCS can also directly regulate autophagic processes. Here, we focus on the nexus between interorganellar contacts and autophagy in yeast and mammalian cells, highlighting similarities and differences. We discuss MCS connecting the ER to mitochondria or the plasma membrane, crucial for early steps of both selective and non-selective autophagy, the yeast-specific nuclear–vacuolar tethering system and its role in microautophagy, the emerging function of distinct autophagy-related proteins in organellar tethering as well as novel MCS transiently emanating from the growing phagophore and mature autophagosome.

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  • 23.
    Kohler, Verena
    et al.
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Probst, Ines
    Division of Infectious Diseases, Department of Internal Medicine, University Medical Center Freiburg, Freiburg, Germany; Faculty of Biology, Microbiology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
    Kohler, Andreas
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Büttner, Sabrina
    Institute of Molecular Biosciences, University of Graz, Graz, Austria; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Schaden, Lisa
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Rechberger, Gerald N.
    Institute of Molecular Biosciences, University of Graz, Graz, Austria; Omics Center Graz, BioTechMed-Graz, Graz, Austria.
    Koraimann, Günther
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Grohmann, Elisabeth
    Division of Infectious Diseases, Department of Internal Medicine, University Medical Center Freiburg, Freiburg, Germany; Faculty of Life Sciences and Technology, Beuth University of Applied Sciences, Berlin, Germany.
    Keller, Walter
    Division of Infectious Diseases, Department of Internal Medicine, University Medical Center Freiburg, Freiburg, Germany; Faculty of Life Sciences and Technology, Beuth University of Applied Sciences, Berlin, Germany.
    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 Gram-positive 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 pIP501ΔtraG. 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.

  • 24.
    Kohler, Verena
    et al.
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Vaishampayan, Ankita
    Life Sciences and Technology, Beuth University of Applied Sciences Berlin, Berlin, Germany.
    Grohmann, Elisabeth
    Beuth University of Applied Sciences Berlin, Faculty of Life Sciences and Technology, Forum Seestrasse, Berlin, Germany.
    Broad-host-range Inc18 plasmids: Occurrence, spread and transfer mechanisms2018In: Plasmid, ISSN 0147-619X, E-ISSN 1095-9890, Vol. 99, p. 11-21Article in journal (Refereed)
    Abstract [en]

    Conjugative plasmid transfer is one of the major mechanisms responsible for the spread of antibiotic resistance and virulence genes. The incompatibility (Inc) 18 group of plasmids is a family of plasmids replicating by the theta-mechanism, whose members have been detected frequently in enterococci and streptococci. Inc18 plasmids encode a variety of antibiotic resistances, including resistance to vancomycin, chloramphenicol and the macrolide-lincosamide-streptogramine (MLS) group of antibiotics. These plasmids comprising insertions of Tn1546 were demonstrated to be responsible for the transfer of vancomycin resistance encoded by the vanA gene from vancomycin resistant enterococci (VRE) to methicillin resistant Staphylococcus aureus (MRSA). Thereby vancomycin resistant S. aureus (VRSA) were generated, which are serious multi-resistant pathogens challenging the health care system. Inc18 plasmids are widespread in the clinic and frequently have been detected in the environment, especially in domestic animals and wastewater. pIP501 is one of the best-characterized conjugative Inc18 plasmids. It was originally isolated from a clinical Streptococcus agalactiae strain and is, due to its small size and simplicity, a model to study conjugative plasmid transfer in Gram-positive bacteria. Here, we report on the occurrence and spread of Inc18-type plasmids in the clinic and in different environments as well as on the exchange of the plasmids among them. In addition, we discuss molecular details on the transfer mechanism of Inc18 plasmids and its regulation, as exemplified by the model plasmid pIP501. We finish with an outlook on promising approaches on how to reduce the emerging spread of antibiotic resistances.

  • 25.
    Kohler, Verena
    et al.
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Vaishampayan, Ankita
    Life Sciences and Technology, Beuth University of Applied Sciences Berlin, Berlin, Germany.
    Grohmann, Elisabeth
    Life Sciences and Technology, Beuth University of Applied Sciences Berlin, Berlin, Germany.
    Problematic groups of multidrug-resistant bacteria and their resistance mechanisms2019In: Antibacterial drug discovery to combat MDR: natural compounds, nanotechnology and novel synthetic sources / [ed] Iqbal Ahmad; Shamim Ahmad; Kendra P. Rumbaugh, Springer Nature, 2019, p. 25-69Chapter in book (Refereed)
    Abstract [en]

    The occurrence of multidrug-resistant pathogenic bacteria is steadily increasing, not only in medical centers but also in food, animals and the environment, which is of primordial concern for health authorities worldwide. The World Health Organization (WHO) published a global pathogen priority list to encourage international interdisciplinary research initiatives on the occurrence, dissemination, and epidemiology of the most dangerous multiresistant pathogens with the aim to develop effective prevention strategies against the spread of these bugs and new therapeutic approaches to treat infections in agreement with the One Health concept. According to the WHO global pathogen priority list, the most critical resistant pathogens include carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa and carbapenem-resistant as well as third-generation cephalosporin-resistant Enterobacteriaceae. This critical group is followed by pathogens of high priority including vancomycin-resistant Enterococcus faecium, methicillin- and vancomycin-resistant Staphylococcus aureus, and clarithromycin-resistant Helicobacter pylori. Here, we summarize recent data on the occurrence and spread of these and other harmful resistant pathogens, on their resistance mechanisms as well as on the modes of resistance spread, as far as is known. We finish the chapter with an outlook on promising innovative strategies to treat infectious diseases caused by multiresistant pathogens – in combination with antibiotic therapy – as well as on approaches to combat the antibiotic resistance spread.

  • 26.
    Kroschwald, Sonja
    et al.
    Institut für Biochemie, ETH Zurich, Zurich, Switzerland.
    Arunagiri, Anoop
    Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.
    Ventura, Salvador
    Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
    Ranganathan, Srivastav
    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, United States.
    Kohler, Verena
    Institute of Molecular Biosciences, University of Graz, Graz, Styria, Austria.
    Editorial: Molecular determinants of protein assemblies in health and disease2022In: Frontiers in Molecular Biosciences, E-ISSN 2296-889X, Vol. 9Article in journal (Other academic)
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  • 27.
    Panagaki, Dimitra
    et al.
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden;.
    Croft, Jacob T.
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden;.
    Keuenhof, Katharina
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden;.
    Larsson Berglund, Lisa
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden;.
    Andersson, Stefanie
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden;.
    Kohler, Verena
    Department of Molecular Bioscienses, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden;.
    Büttner, Sabrina
    Department of Molecular Bioscienses, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden;.
    Tamás, Markus J.
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden;.
    Nyström, Thomas
    Department of Microbiology and Immunology, University of Gothenburg, Gothenburg, Sweden.
    Neutze, Richard
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden;.
    Höög, Johanna L.
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden;.
    Nuclear envelope budding is a response to cellular stress2021In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, no 30, article id e2020997118Article in journal (Refereed)
    Abstract [en]

    Nuclear envelope budding (NEB) is a recently discovered alternative pathway for nucleocytoplasmic communication distinct from the movement of material through the nuclear pore complex. Through quantitative electron microscopy and tomography, we demonstrate how NEB is evolutionarily conserved from early protists to human cells. In the yeast Saccharomyces cerevisiae, NEB events occur with higher frequency during heat shock, upon exposure to arsenite or hydrogen peroxide, and when the proteasome is inhibited. Yeast cells treated with azetidine-2-carboxylic acid, a proline analog that induces protein misfolding, display the most dramatic increase in NEB, suggesting a causal link to protein quality control. This link was further supported by both localization of ubiquitin and Hsp104 to protein aggregates and NEB events, and the evolution of these structures during heat shock. We hypothesize that NEB is part of normal cellular physiology in a vast range of species and that in S. cerevisiae NEB comprises a stress response aiding the transport of protein aggregates across the nuclear envelope.

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  • 28.
    Peselj, Carlotta
    et al.
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Ebrahimi, Mahsa
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Broeskamp, Filomena
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Prokisch, Simon
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Habernig, Lukas
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Alvarez-Guerra, Irene
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Kohler, Verena
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Vögtle, F.-Nora
    Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg, Germany; Network Aging Research, Heidelberg University, Heidelberg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
    Büttner, Sabrina
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Sterol metabolism differentially contributes to maintenance and exit of quiescence2022In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 10, article id 788472Article in journal (Refereed)
    Abstract [en]

    Nutrient starvation initiates cell cycle exit and entry into quiescence, a reversible, non-proliferative state characterized by stress tolerance, longevity and large-scale remodeling of subcellular structures. Depending on the nature of the depleted nutrient, yeast cells are assumed to enter heterogeneous quiescent states with unique but mostly unexplored characteristics. Here, we show that storage and consumption of neutral lipids in lipid droplets (LDs) differentially impacts the regulation of quiescence driven by glucose or phosphate starvation. Upon prolonged glucose exhaustion, LDs were degraded in the vacuole via Atg1-dependent lipophagy. In contrast, yeast cells entering quiescence due to phosphate exhaustion massively over-accumulated LDs that clustered at the vacuolar surface but were not engulfed via lipophagy. Excessive LD biogenesis required contact formation between the endoplasmic reticulum and the vacuole at nucleus-vacuole junctions and was accompanied by a shift of the cellular lipid profile from membrane towards storage lipids, driven by a transcriptional upregulation of enzymes generating neutral lipids, in particular sterol esters. Importantly, sterol ester biogenesis was critical for long-term survival of phosphate-exhausted cells and supported rapid quiescence exit upon nutrient replenishment, but was dispensable for survival and regrowth of glucose-exhausted cells. Instead, these cells relied on de novo synthesis of sterols and fatty acids for quiescence exit and regrowth. Phosphate-exhausted cells efficiently mobilized storage lipids to support several rounds of cell division even in presence of inhibitors of fatty acid and sterol biosynthesis. In sum, our results show that neutral lipid biosynthesis and mobilization to support quiescence maintenance and exit is tailored to the respective nutrient scarcity.

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  • 29. Tosal-Castano, Sergi
    et al.
    Peselj, Carlotta
    Kohler, Verena
    Department of Molecular Biosciences, The Wenner-Gren Institute, StockholmUniversity, Stockholm, Sweden.
    Habernig, Lukas
    Berglund, Lisa Larsson
    Ebrahimi, Mahsa
    Vögtle, F.-Nora
    Höög, Johanna
    Andréasson, Claes
    Büttner, Sabrina
    Snd3 controls nucleus-vacuole junctions in response to glucose signaling2021In: Cell Reports, E-ISSN 2211-1247, Vol. 34, no 3, article id 108637Article in journal (Refereed)
    Abstract [en]

    Membrane contact sites facilitate the exchange of metabolites between organelles to support interorganellar communication. The nucleus-vacuole junctions (NVJs) establish physical contact between the perinuclear endoplasmic reticulum (ER) and the vacuole. Although the NVJ tethers are known, how NVJ abundance and composition are controlled in response to metabolic cues remains elusive. Here, we identify the ER protein Snd3 as central factor for NVJ formation. Snd3 interacts with NVJ tethers, supports their targeting to the contacts, and is essential for NVJ formation. Upon glucose exhaustion, Snd3 relocalizes from the ER to NVJs and promotes contact expansion regulated by central glucose signaling pathways. Glucose replenishment induces the rapid dissociation of Snd3 from the NVJs, preceding the slow disassembly of the junctions. In sum, this study identifies a key factor required for formation and regulation of NVJs and provides a paradigm for metabolic control of membrane contact sites.

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  • 30.
    Vazquez‐Calvo, Carmela
    et al.
    Department of Biochemistry and Biophysics Stockholm University Stockholm Sweden; Department of Molecular Biosciences, The Wenner‐Gren Institute Stockholm University Stockholm Sweden.
    Kohler, Verena
    Department of Molecular Biosciences, The Wenner‐Gren Institute Stockholm University Stockholm Sweden; Institute of Molecular Biosciences University of Graz Graz Austria.
    Höög, Johanna L.
    Department of Chemistry and Molecular Biology University of Gothenburg Gothenburg Sweden.
    Büttner, Sabrina
    Department of Molecular Biosciences, The Wenner‐Gren Institute Stockholm University Stockholm Sweden.
    Ott, Martin
    Department of Biochemistry and Biophysics Stockholm University Stockholm Sweden; Department of Medical Biochemistry and Cell Biology University of Gothenburg Gothenburg Sweden.
    Newly imported proteins in mitochondria are particularly sensitive to aggregation2023In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 238, no 3, article id e13985Article in journal (Refereed)
    Abstract [en]

    Aim: A functional proteome is essential for life and maintained by protein quality control (PQC) systems in the cytosol and organelles. Protein aggregation is an indicator of a decline of PQC linked to aging and disease. Mitochondrial PQC is critical to maintain mitochondrial function and thus cellular fitness. How mitochondria handle aggregated proteins is not well understood. Here we tested how the metabolic status impacts on formation and clearance of aggregates within yeast mitochondria and assessed which proteins are particularly sensitive to denaturation.

    Methods: Confocal microscopy, electron microscopy, immunoblotting and genetics were applied to assess mitochondrial aggregate handling in response to heat shock and ethanol using the mitochondrial disaggregase Hsp78 as a marker for protein aggregates.

    Results: We show that aggregates formed upon heat or ethanol stress with different dynamics depending on the metabolic state. While fermenting cells displayed numerous small aggregates that coalesced into one large foci that was resistant to clearance, respiring cells showed less aggregates and cleared these aggregates more efficiently. Acute inhibition of mitochondrial translation had no effect, while preventing protein import into mitochondria by inhibition of cytosolic translation prevented aggregate formation.

    Conclusion: Collectively, our data show that the metabolic state of the cells impacts the dynamics of aggregate formation and clearance, and that mainly newly imported and not yet assembled proteins are prone to form aggregates. Because mitochondrial functionality is crucial for cellular metabolism, these results highlight the importance of efficient protein biogenesis to maintain the mitochondrial proteome operational during metabolic adaptations and cellular stress.

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