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Kohler, Andreas, Dr. rer. nat.ORCID iD iconorcid.org/0000-0001-6571-2162
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Publications (10 of 27) Show all publications
Kohler, V., Kohler, A., Berglund, L. L., Hao, X., Gersing, S., Imhof, A., . . . Büttner, S. (2024). Nuclear Hsp104 safeguards the dormant translation machinery during quiescence. Nature Communications, 15(1), Article ID 315.
Open this publication in new window or tab >>Nuclear Hsp104 safeguards the dormant translation machinery during quiescence
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2024 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 15, no 1, article id 315Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer Nature, 2024
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-219058 (URN)10.1038/s41467-023-44538-8 (DOI)38182580 (PubMedID)2-s2.0-85181445502 (Scopus ID)
Funder
Swedish Research Council, 2019-05249Swedish Research Council, 2019-04004Swedish Research Council, 2019-04052Knut and Alice Wallenberg Foundation, 2017.009Olle Engkvists stiftelse, 207-0527Swedish Cancer Society, 211865Swedish Cancer Society, 201045Swedish Cancer Society, 222488
Available from: 2024-01-07 Created: 2024-01-07 Last updated: 2024-01-25Bibliographically approved
Kohler, A., Carlström, A., Nolte, H., Kohler, V., Jung, S.-j., Sridhara, S., . . . Ott, M. (2023). Early fate decision for mitochondrially encoded proteins by a molecular triage. Molecular Cell, 83(19), 3470-3484
Open this publication in new window or tab >>Early fate decision for mitochondrially encoded proteins by a molecular triage
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2023 (English)In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 83, no 19, p. 3470-3484Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Cell Press, 2023
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-214999 (URN)10.1016/j.molcel.2023.09.001 (DOI)
Available from: 2023-10-05 Created: 2023-10-05 Last updated: 2023-10-16Bibliographically approved
Kohler, V., Braun, R. J. & Kohler, A. (2023). Editorial: Mitochondria as a hub for neurodegenerative disorders. Frontiers in Molecular Neuroscience, 16, Article ID 1147468.
Open this publication in new window or tab >>Editorial: Mitochondria as a hub for neurodegenerative disorders
2023 (English)In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 16, article id 1147468Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-215003 (URN)10.3389/fnmol.2023.1147468 (DOI)000935069000001 ()2-s2.0-85148508309 (Scopus ID)
Available from: 2023-10-05 Created: 2023-10-05 Last updated: 2023-10-16Bibliographically approved
Kohler, A., Barrientos, A., Fontanesi, F. & Ott, M. (2023). The functional significance of mitochondrial respiratory chain supercomplexes. EMBO Reports, Article ID e57092.
Open this publication in new window or tab >>The functional significance of mitochondrial respiratory chain supercomplexes
2023 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, article id e57092Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
EMBO Press, 2023
Keywords
bioenergetics; electron transfer; Mitochondria; respiratory chain; supercomplexes
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-215332 (URN)10.15252/embr.202357092 (DOI)
Funder
NIH (National Institutes of Health), GM118141Knut and Alice Wallenberg Foundation, 2019.0319Knut and Alice Wallenberg Foundation, 2017.0091Swedish Research Council, 2014‐4116Swedish Research Council, 2018‐03694
Available from: 2023-10-18 Created: 2023-10-18 Last updated: 2023-10-18Bibliographically approved
Aufschnaiter, A., Carlström, A. & Ott, M. (2023). Yeast Mitoribosome Purification and Analyses by Sucrose Density Centrifugation and Immunoprecipitation. In: Antoni Barrientos and Flavia Fontanesi (Ed.), The Mitoribosome: Methods and Protocols (pp. 119-132). Humana Press
Open this publication in new window or tab >>Yeast Mitoribosome Purification and Analyses by Sucrose Density Centrifugation and Immunoprecipitation
2023 (English)In: 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.

Place, publisher, year, edition, pages
Humana Press, 2023
Series
Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029 ; 2661
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-215177 (URN)10.1007/978-1-0716-3171-3_8 (DOI)37166635 (PubMedID)2-s2.0-85159451845 (Scopus ID)978-1-0716-3170-6 (ISBN)978-1-0716-3171-3 (ISBN)
Available from: 2023-10-10 Created: 2023-10-10 Last updated: 2023-10-10Bibliographically approved
Aufschnaiter, A. & Ott, M. (2022). Fließbandfertigung von Atmungskettenkomplexen in Mitochondrien. BIOspektrum, 28(4), 366-369
Open this publication in new window or tab >>Fließbandfertigung von Atmungskettenkomplexen in Mitochondrien
2022 (German)In: BIOspektrum, ISSN 0947-0867, Vol. 28, no 4, p. 366-369Article in journal (Other academic) Published
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.

Place, publisher, year, edition, pages
Springer Nature, 2022
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-215189 (URN)10.1007/s12268-022-1783-9 (DOI)2-s2.0-85132125915 (Scopus ID)
Available from: 2023-10-10 Created: 2023-10-10 Last updated: 2023-10-10Bibliographically approved
Dickinson, Q., Kohler, A., Ott, M. & Meyer, J. G. (2022). Multi-omic integration by machine learning (MIMaL). Bioinformatics, 38(21), 4908-4918
Open this publication in new window or tab >>Multi-omic integration by machine learning (MIMaL)
2022 (English)In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 38, no 21, p. 4908-4918Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Oxford University Press, 2022
National Category
Natural Sciences
Identifiers
urn:nbn:se:umu:diva-215178 (URN)10.1093/bioinformatics/btac631 (DOI)000862056200001 ()36106996 (PubMedID)2-s2.0-85141003942 (Scopus ID)
Funder
NIH (National Institutes of Health), R35 GM142502Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2023-10-10 Created: 2023-10-10 Last updated: 2023-10-10Bibliographically approved
Saini, P. K., Dawitz, H., Kohler, A., Bondarev, S., Thomas, J., Amblard, A., . . . Pierrel, F. (2022). The [PSI+] prion modulates cytochrome c oxidase deficiency caused by deletion of COX12. Molecular Biology of the Cell, 33(14), Article ID 130.
Open this publication in new window or tab >>The [PSI+] prion modulates cytochrome c oxidase deficiency caused by deletion of COX12
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2022 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 33, no 14, article id 130Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Society for Cell Biology (ASCB), 2022
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-215180 (URN)10.1091/mbc.e21-10-0499 (DOI)000890129900006 ()36129767 (PubMedID)2-s2.0-85142403724 (Scopus ID)
Available from: 2023-10-10 Created: 2023-10-10 Last updated: 2023-10-10Bibliographically approved
Habernig, L., Broeskamp, F., Aufschnaiter, A., Diessl, J., Peselj, C., Urbauer, E., . . . Büttner, S. (2021). Ca2+ administration prevents α-synuclein proteotoxicity by stimulating calcineurin-dependent lysosomal proteolysis. PLOS Genetics, 17(11), Article ID e1009911.
Open this publication in new window or tab >>Ca2+ administration prevents α-synuclein proteotoxicity by stimulating calcineurin-dependent lysosomal proteolysis
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2021 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 17, no 11, article id e1009911Article in journal (Refereed) Published
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. 

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2021
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-215181 (URN)10.1371/journal.pgen.1009911 (DOI)000727767200006 ()34780474 (PubMedID)2-s2.0-85119910139 (Scopus ID)
Funder
Swedish Research Council, 2015-05468Swedish Research Council, 2019-05249Knut and Alice Wallenberg Foundation, 2017.0091Olle Engkvists stiftelse, 194-0681
Available from: 2023-10-10 Created: 2023-10-10 Last updated: 2023-10-10Bibliographically approved
Ebrahimi, M., Habernig, L., Broeskamp, F., Aufschnaiter, A., Diessl, J., Atienza, I., . . . Büttner, S. (2021). Phosphate Restriction Promotes Longevity via Activation of Autophagy and the Multivesicular Body Pathway. Cells, 10(11), Article ID 3161.
Open this publication in new window or tab >>Phosphate Restriction Promotes Longevity via Activation of Autophagy and the Multivesicular Body Pathway
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2021 (English)In: Cells, E-ISSN 2073-4409, Vol. 10, no 11, article id 3161Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
lifespan, nutrient limitation, yeast, autophagy, Pho85, aging, polyphosphate, vacuole fusion, quiescence
National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:umu:diva-215182 (URN)10.3390/cells10113161 (DOI)000724895300001 ()34831384 (PubMedID)2-s2.0-85118944549 (Scopus ID)
Funder
Swedish Research Council, 2015-05468Swedish Research Council, 2019-05249Knut and Alice Wallenberg Foundation, 2017.009Olle Engkvists stiftelse, 194-0681Olle Engkvists stiftelse, 207-0527
Available from: 2023-10-10 Created: 2023-10-10 Last updated: 2023-10-12Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-6571-2162

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