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  • 1.
    Aufschnaiter, Andreas
    et al.
    Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
    Büttner, Sabrina
    Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
    Peroxisomal fission controls yeast life span2015In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 14, no 15, p. 2389-2390Article in journal (Refereed)
  • 2.
    Aufschnaiter, Andreas
    et al.
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Carlström, Andreas
    Department of Biochemistry and Biophysics, 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.
    Yeast Mitoribosome Purification and Analyses by Sucrose Density Centrifugation and Immunoprecipitation2023In: The Mitoribosome: Methods and Protocols / [ed] Antoni Barrientos and Flavia Fontanesi, Humana Press, 2023, p. 119-132Chapter in book (Other academic)
    Abstract [en]

    Mitochondrial protein biosynthesis is maintained by an interplay between the mitochondrial ribosome (mitoribosome) and a large set of protein interaction partners. This interactome regulates a diverse set of functions, including mitochondrial gene expression, translation, protein quality control, and respiratory chain assembly. Hence, robust methods to biochemically and structurally analyze this molecular machinery are required to understand the sophisticated regulation of mitochondrial protein biosynthesis. In this chapter, we present detailed protocols for immunoprecipitation, sucrose cushions, and linear sucrose gradients to purify and analyze mitoribosomes and their interaction partners.

  • 3.
    Aufschnaiter, Andreas
    et al.
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden; Department of Medical Biochemistry and Cell Biology Institute for Biomedicine Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Ott, Martin
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden; Department of Medical Biochemistry and Cell Biology Institute for Biomedicine Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Fließbandfertigung von Atmungskettenkomplexen in Mitochondrien2022In: BIOspektrum, ISSN 0947-0867, Vol. 28, no 4, p. 366-369Article in journal (Other academic)
    Abstract [en]

    A key function of mitochondria consists of energy conversion, performed with the help of the respiratory chain and the ATP synthase. Biogenesis of these essential molecular machines requires expression of nuclear and mitochondrially encoded genes. We describe our current understanding how these processes are coordinated and how they are organized in specific areas of the inner membrane to facilitate the assembly of these sophisticated complexes.

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  • 4.
    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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  • 5.
    Dickinson, Quinn
    et al.
    Department of Biochemistry, Medical College of Wisconsin, Milwaukee, USA; Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, USA.
    Kohler, Andreas
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    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.
    Meyer, Jesse G
    Department of Biochemistry, Medical College of Wisconsin, Milwaukee, USA; Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, USA.
    Multi-omic integration by machine learning (MIMaL)2022In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 38, no 21, p. 4908-4918Article in journal (Refereed)
    Abstract [en]

    Motivation: Cells respond to environments by regulating gene expression to exploit resources optimally. Recent advances in technologies allow for measuring the abundances of RNA, proteins, lipids and metabolites. These highly complex datasets reflect the states of the different layers in a biological system. Multi-omics is the integration of these disparate methods and data to gain a clearer picture of the biological state. Multi-omic studies of the proteome and metabolome are becoming more common as mass spectrometry technology continues to be democratized. However, knowledge extraction through the integration of these data remains challenging.

    Results: Connections between molecules in different omic layers were discovered through a combination of machine learning and model interpretation. Discovered connections reflected protein control (ProC) over metabolites. Proteins discovered to control citrate were mapped onto known genetic and metabolic networks, revealing that these protein regulators are novel. Further, clustering the magnitudes of ProC over all metabolites enabled the prediction of five gene functions, each of which was validated experimentally. Two uncharacterized genes, YJR120W and YDL157C, were accurately predicted to modulate mitochondrial translation. Functions for three incompletely characterized genes were also predicted and validated, including SDH9, ISC1 and FMP52. A website enables results exploration and also MIMaL analysis of user-supplied multi-omic data.

  • 6.
    Ebrahimi, Mahsa
    et al.
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, 106 91, Sweden.
    Habernig, Lukas
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, 106 91, Sweden.
    Broeskamp, Filomena
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, 106 91, Sweden.
    Aufschnaiter, Andreas
    Department of Biochemistry and Biophysics, Stockholm University, 106 91 Stockholm, Sweden.
    Diessl, Jutta
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, 106 91, Sweden.
    Atienza, Isabel
    Instituto de Investigación e Innovación Biomédica de Cádiz (INIBICA), University of Cadiz, 11001 Cadiz, Spain.
    Matz, Steffen
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden.
    Ruiz, Felix A.
    Instituto de Investigación e Innovación Biomédica de Cádiz (INIBICA), University of Cadiz, 11001 Cadiz, Spain.
    Büttner, Sabrina
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden; Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
    Phosphate Restriction Promotes Longevity via Activation of Autophagy and the Multivesicular Body Pathway2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 11, article id 3161Article in journal (Refereed)
    Abstract [en]

    Nutrient limitation results in an activation of autophagy in organisms ranging from yeast, nematodes and flies to mammals. Several evolutionary conserved nutrient-sensing kinases are critical for efficient adaptation of yeast cells to glucose, nitrogen or phosphate depletion, subsequent cell-cycle exit and the regulation of autophagy. Here, we demonstrate that phosphate restriction results in a prominent extension of yeast lifespan that requires the coordinated activity of autophagy and the multivesicular body pathway, enabling efficient turnover of cytoplasmic and plasma membrane cargo. While the multivesicular body pathway was essential during the early days of aging, autophagy contributed to long-term survival at later days. The cyclin-dependent kinase Pho85 was critical for phosphate restriction-induced autophagy and full lifespan extension. In contrast, when cell-cycle exit was triggered by exhaustion of glucose instead of phosphate, Pho85 and its cyclin, Pho80, functioned as negative regulators of autophagy and lifespan. The storage of phosphate in form of polyphosphate was completely dispensable to in sustaining viability under phosphate restriction. Collectively, our results identify the multifunctional, nutrient-sensing kinase Pho85 as critical modulator of longevity that differentially coordinates the autophagic response to distinct kinds of starvation.

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  • 7. Gross, Angelina S.
    et al.
    Zimmermann, Andreas
    Pendl, Tobias
    Schroeder, Sabrina
    Schoenlechner, Hannes
    Knittelfelder, Oskar
    Lamplmayr, Laura
    Santiso, Ana
    Aufschnaiter, Andreas
    Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria; Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    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
    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 (acc1S/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, acc1S/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 acc1S/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.

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  • 8.
    Habernig, Lukas
    et al.
    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.
    Aufschnaiter, Andreas
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    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.
    Urbauer, Elisabeth
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Eisenberg, Tobias
    Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria; Field of Excellence BioHealth–University of Graz, Graz, Austria.
    de Ory, Ana
    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.
    Ca2+ administration prevents α-synuclein proteotoxicity by stimulating calcineurin-dependent lysosomal proteolysis2021In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 17, no 11, article id e1009911Article in journal (Refereed)
    Abstract [en]

    The capacity of a cell to maintain proteostasis progressively declines during aging. Virtually all age-associated neurodegenerative disorders associated with aggregation of neurotoxic proteins are linked to defects in the cellular proteostasis network, including insufficient lysosomal hydrolysis. Here, we report that proteotoxicity in yeast and Drosophila models for Parkinson's disease can be prevented by increasing the bioavailability of Ca2+, which adjusts intracellular Ca2+ handling and boosts lysosomal proteolysis. Heterologous expression of human α-synuclein (αSyn), a protein critically linked to Parkinson's disease, selectively increases total cellular Ca2+ content, while the levels of manganese and iron remain unchanged. Disrupted Ca2+ homeostasis results in inhibition of the lysosomal protease cathepsin D and triggers premature cellular and organismal death. External administration of Ca2+ reduces αSyn oligomerization, stimulates cathepsin D activity and in consequence restores survival, which critically depends on the Ca2+/calmodulin-dependent phosphatase calcineurin. In flies, increasing the availability of Ca2+ discloses a neuroprotective role of αSyn upon manganese overload. In sum, we establish a molecular interplay between cathepsin D and calcineurin that can be activated by Ca2+ administration to counteract αSyn proteotoxicity. 

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  • 9.
    Kohler, Andreas
    et al.
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden; Institute of Molecular Biosciences University of Graz, Graz, Austria.
    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.
    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.
    The functional significance of mitochondrial respiratory chain supercomplexes2023In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, article id e57092Article in journal (Refereed)
    Abstract [en]

    The mitochondrial respiratory chain (MRC) is a key energy transducer in eukaryotic cells. Four respiratory chain complexes cooperate in the transfer of electrons derived from various metabolic pathways to molecular oxygen, thereby establishing an electrochemical gradient over the inner mitochondrial membrane that powers ATP synthesis. This electron transport relies on mobile electron carries that functionally connect the complexes. While the individual complexes can operate independently, they are in situ organized into large assemblies termed respiratory supercomplexes. Recent structural and functional studies have provided some answers to the question of whether the supercomplex organization confers an advantage for cellular energy conversion. However, the jury is still out, regarding the universality of these claims. In this review, we discuss the current knowledge on the functional significance of MRC supercomplexes, highlight experimental limitations, and suggest potential new strategies to overcome these obstacles.

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  • 10.
    Kohler, Andreas
    et al.
    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.
    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 in journal (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.

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  • 11. 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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  • 12. 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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  • 13. 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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  • 14. 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. 

  • 15.
    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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  • 16. 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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  • 17.
    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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  • 18.
    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)
  • 19.
    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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  • 20.
    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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  • 21.
    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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  • 22.
    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.

  • 23. Leibiger, Christine
    et al.
    Deisel, Jana
    Aufschnaiter, Andreas
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Ambros, Stefanie
    Tereshchenko, Maria
    Verheijen, Bert M.
    Buettner, Sabrina
    Braun, Ralf J.
    Endolysosomal pathway activity protects cells from neurotoxic TDP-432018In: Microbial Cell, E-ISSN 2311-2638, Vol. 5, no 4, p. 212-214Article in journal (Other academic)
    Abstract [en]

    The accumulation of protein aggregates in neurons is a typical pathological hallmark of the motor neuron disease amyotrophic lateral sclerosis (ALS) and of frontotemporal dementia (FTD). In many cases, these aggregates are composed of the 43 kDa TAR DNA-binding protein (TDP‑43). Using a yeast model for TDP‑43 proteinopathies, we observed that the vacuole (the yeast equivalent of lysosomes) markedly contributed to the degradation of TDP‑43. This clearance occurred via TDP‑43-containing vesicles fusing with the vacuole through the concerted action of the endosomal-vacuolar (or endolysosomal) pathway and autophagy. In line with its dominant role in the clearance of TDP‑43, endosomal-vacuolar pathway activity protected cells from the detrimental effects of TDP‑43. In contrast, enhanced autophagy contributed to TDP‑43 cytotoxicity, despite being involved in TDP‑43 degradation. TDP‑43’s interference with endosomal-vacuolar pathway activity may have two deleterious consequences. First, it interferes with its own degradation via this pathway, resulting in TDP‑43 accumulation. Second, it affects vacuolar proteolytic activity, which requires endosomal-vacuolar trafficking. We speculate that the latter contributes to aberrant autophagy. In sum, we propose that ameliorating endolysosomal pathway activity enhances cell survival in TDP‑43-associated diseases.

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  • 24.
    Leibiger, Christine
    et al.
    Institute of Cell Biology, University of Bayreuth, Bayreuth, Germany.
    Deisel, Jana
    Institute of Cell Biology, University of Bayreuth, Bayreuth, Germany.
    Aufschnaiter, Andreas
    Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Ambros, Stefanie
    Institute of Cell Biology, University of Bayreuth, Bayreuth, Germany.
    Tereshchenko, Maria
    Institute of Cell Biology, University of Bayreuth, Bayreuth, Germany.
    Verheijen, Bert M.
    Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
    Büttner, Sabrina
    Institute of Molecular Biosciences, University of Graz, Graz, Austria; Department of Molecular Biosciences, The Wenner Gren Institute, Stockholm University, Stockholm, Sweden.
    Braun, Ralf J.
    Institute of Cell Biology, University of Bayreuth, Bayreuth, Germany.
    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.

  • 25.
    Saini, Pawan Kumar
    et al.
    Université Grenoble-Alpes, Grenoble, France.
    Dawitz, Hannah
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Kohler, Andreas
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Bondarev, Stanislav
    Department of Genetics and Biotechnology, St. Petersburg State University, St. Petersburg, Russia.
    Thomas, Jinsu
    Université Grenoble-Alpes, Grenoble, France.
    Amblard, Amélie
    Université Grenoble-Alpes, Grenoble, France.
    Stewart, James
    Max Planck Institute for Biology of Ageing, Cologne, Germany; Wellcome Centre for Mitochondrial Research, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
    Thierry-Mieg, Nicolas
    Université Grenoble-Alpes, Grenoble, France.
    Ott, Martin
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.
    Pierrel, Fabien
    Université Grenoble-Alpes, Grenoble, France.
    The [PSI+] prion modulates cytochrome c oxidase deficiency caused by deletion of COX122022In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 33, no 14, article id 130Article in journal (Refereed)
    Abstract [en]

    Cytochrome c oxidase (CcO) is a pivotal enzyme of the mitochondrial respiratory chain, which sustains bioenergetics of eukaryotic cells. Cox12, a peripheral subunit of CcO oxidase, is required for full activity of the enzyme, but its exact function is unknown. Here experimental evolution of a Saccharomyces cerevisiae Δcox12 strain for ∼300 generations allowed to restore the activity of CcO oxidase. In one population, the enhanced bioenergetics was caused by a A375V mutation in the cytosolic AAA+ disaggregase Hsp104. Deletion or overexpression of HSP104 also increased respiration of the Δcox12 ancestor strain. This beneficial effect of Hsp104 was related to the loss of the [PSI+] prion, which forms cytosolic amyloid aggregates of the Sup35 protein. Overall, our data demonstrate that cytosolic aggregation of a prion impairs the mitochondrial metabolism of cells defective for Cox12. These findings identify a new functional connection between cytosolic proteostasis and biogenesis of the mitochondrial respiratory chain.

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  • 26.
    Singh, Abeer Prakash
    et al.
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.
    Salvatori, Roger
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.
    Aftab, Wasim
    BioMedical Center, Faculty of Medicine, Ludwig Maximilians University of Munich, Planegg-Martinsried, Germany; Graduate School for Quantitative Biosciences (QBM), Ludwig Maximilians University of Munich, Munich, Germany.
    Kohler, Andreas
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Carlström, Andreas
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Forne, Ignasi
    BioMedical Center, Faculty of Medicine, Ludwig Maximilians University of Munich, Planegg-Martinsried, Germany.
    Imhof, Axel
    BioMedical Center, Faculty of Medicine, Ludwig Maximilians University of Munich, Planegg-Martinsried, Germany.
    Ott, Martin
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.
    Molecular Connectivity of Mitochondrial Gene Expression and OXPHOS Biogenesis2020In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 79, no 6, p. 1051-1065.e10Article in journal (Refereed)
    Abstract [en]

    Mitochondria contain their own gene expression systems, including membrane-bound ribosomes dedicated to synthesizing a few hydrophobic subunits of the oxidative phosphorylation (OXPHOS) complexes. We used a proximity-dependent biotinylation technique, BioID, coupled with mass spectrometry to delineate in baker’s yeast a comprehensive network of factors involved in biogenesis of mitochondrial encoded proteins. This mitochondrial gene expression network (MiGENet) encompasses proteins involved in transcription, RNA processing, translation, or protein biogenesis. Our analyses indicate the spatial organization of these processes, thereby revealing basic mechanistic principles and the proteins populating strategically important sites. For example, newly synthesized proteins are directly handed over to ribosomal tunnel exit-bound factors that mediate membrane insertion, co-factor acquisition, or their mounting into OXPHOS complexes in a special early assembly hub. Collectively, the data reveal the connectivity of mitochondrial gene expression, reflecting a unique tailoring of the mitochondrial gene expression system.

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  • 27.
    Toth, Alexandra
    et al.
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Stockholm, Sweden.
    Aufschnaiter, Andreas
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Stockholm, Sweden; Institute of Molecular Biosciences, University of Graz, Graz, Austria.
    Fedotovskaya, Olga
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Stockholm, Sweden.
    Dawitz, Hannah
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Stockholm, Sweden.
    Ädelroth, Pia
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Stockholm, Sweden.
    Büttner, Sabrina
    Institute of Molecular Biosciences, University of Graz, Graz, Austria; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Ott, Martin
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Stockholm, Sweden.
    Membrane-tethering of cytochrome c accelerates regulated cell death in yeast2020In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 11, no 9, article id 722Article in journal (Refereed)
    Abstract [en]

    Intrinsic apoptosis as a modality of regulated cell death is intimately linked to permeabilization of the outer mitochondrial membrane and subsequent release of the protein cytochrome c into the cytosol, where it can participate in caspase activation via apoptosome formation. Interestingly, cytochrome c release is an ancient feature of regulated cell death even in unicellular eukaryotes that do not contain an apoptosome. Therefore, it was speculated that cytochrome c release might have an additional, more fundamental role for cell death signalling, because its absence from mitochondria disrupts oxidative phosphorylation. Here, we permanently anchored cytochrome c with a transmembrane segment to the inner mitochondrial membrane of the yeast Saccharomyces cerevisiae, thereby inhibiting its release from mitochondria during regulated cell death. This cytochrome c retains respiratory growth and correct assembly of mitochondrial respiratory chain supercomplexes. However, membrane anchoring leads to a sensitisation to acetic acid-induced cell death and increased oxidative stress, a compensatory elevation of cellular oxygen-consumption in aged cells and a decreased chronological lifespan. We therefore conclude that loss of cytochrome c from mitochondria during regulated cell death and the subsequent disruption of oxidative phosphorylation is not required for efficient execution of cell death in yeast, and that mobility of cytochrome c within the mitochondrial intermembrane space confers a fitness advantage that overcomes a potential role in regulated cell death signalling in the absence of an apoptosome.

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