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Publications (10 of 30) 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, V., Arunagiri, A., Ventura, S., Kroschwald, S. & Ranganathan, S. (2023). Editorial: molecular determinants of protein assemblies in health and disease, volume II. Frontiers in Molecular Biosciences, 10, Article ID 1343082.
Open this publication in new window or tab >>Editorial: molecular determinants of protein assemblies in health and disease, volume II
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2023 (English)In: Frontiers in Molecular Biosciences, E-ISSN 2296-889X, Vol. 10, article id 1343082Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
amyloid, chaperones, disaggregation, protein aggregation, RT QuIC
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-219106 (URN)10.3389/fmolb.2023.1343082 (DOI)2-s2.0-85180639554 (Scopus ID)
Available from: 2024-01-10 Created: 2024-01-10 Last updated: 2024-01-10Bibliographically approved
Vazquez‐Calvo, C., Kohler, V., Höög, J. L., Büttner, S. & Ott, M. (2023). Newly imported proteins in mitochondria are particularly sensitive to aggregation. Acta Physiologica, 238(3), Article ID e13985.
Open this publication in new window or tab >>Newly imported proteins in mitochondria are particularly sensitive to aggregation
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2023 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 238, no 3, article id e13985Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
aggregates, aging, cellular stress, Hsp78, metabolism, mitochondria, protein quality control, proteostasis
National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:umu:diva-215000 (URN)10.1111/apha.13985 (DOI)000999348700001 ()37171464 (PubMedID)2-s2.0-85161389474 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2019.0319Knut and Alice Wallenberg Foundation, 2017.009Olle Engkvists stiftelse, 207‐0527Swedish Cancer Society, 22 2488
Available from: 2023-10-05 Created: 2023-10-05 Last updated: 2023-10-09Bibliographically approved
Keuenhof, K. S., Kohler, V., Broeskamp, F., Panagaki, D., Speese, S. D., Büttner, S. & Höög, J. L. (2023). Nuclear envelope budding and its cellular functions. Nucleus, 14(1), Article ID 2178184.
Open this publication in new window or tab >>Nuclear envelope budding and its cellular functions
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2023 (English)In: Nucleus, ISSN 1949-1034, E-ISSN 1949-1042, Vol. 14, no 1, article id 2178184Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2023
Keywords
Nuclear import, nuclear export, nuclear envelope budding
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-214997 (URN)10.1080/19491034.2023.2178184 (DOI)000938016800001 ()36814098 (PubMedID)2-s2.0-85148550269 (Scopus ID)
Funder
Swedish Cancer Society, 21 1865Swedish Cancer Society, 22 2488Knut and Alice Wallenberg Foundation, 2017.009Olle Engkvists stiftelse, 207-0527Swedish Research Council, 2019-04004Swedish Research Council, 2019-05249Swedish Research Council, 2015-00560
Available from: 2023-10-05 Created: 2023-10-05 Last updated: 2023-10-09Bibliographically approved
Kohler, V. & Andréasson, C. (2023). Reversible protein assemblies in the proteostasis network in health and disease. Frontiers in Molecular Biosciences, 10, Article ID 1155521.
Open this publication in new window or tab >>Reversible protein assemblies in the proteostasis network in health and disease
2023 (English)In: Frontiers in Molecular Biosciences, E-ISSN 2296-889X, Vol. 10, article id 1155521Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
phase separation, biomolecular condensate, aggregate, Hsp70, Hsp100, disaggregation, refolding, degradation
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-215002 (URN)10.3389/fmolb.2023.1155521 (DOI)000962292900001 ()37021114 (PubMedID)2-s2.0-85152561061 (Scopus ID)
Funder
Swedish Research Council, 2019-04052Knut and Alice Wallenberg FoundationSwedish Cancer Society, 20 1045
Available from: 2023-10-05 Created: 2023-10-05 Last updated: 2023-10-09Bibliographically approved
Kroschwald, S., Arunagiri, A., Ventura, S., Ranganathan, S. & Kohler, V. (2022). Editorial: Molecular determinants of protein assemblies in health and disease. Frontiers in Molecular Biosciences, 9
Open this publication in new window or tab >>Editorial: Molecular determinants of protein assemblies in health and disease
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2022 (English)In: Frontiers in Molecular Biosciences, E-ISSN 2296-889X, Vol. 9Article in journal, Editorial material (Other academic) Published
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-215004 (URN)10.3389/fmolb.2022.1107686 (DOI)000905112000001 ()2-s2.0-85145040725 (Scopus ID)
Available from: 2023-10-05 Created: 2023-10-05 Last updated: 2023-10-09Bibliographically approved
Diessl, J., Berndtsson, J., Broeskamp, F., Habernig, L., Kohler, V., Vazquez-Calvo, C., . . . Büttner, S. (2022). Manganese-driven CoQ deficiency. Nature Communications, 13(1), Article ID 6061.
Open this publication in new window or tab >>Manganese-driven CoQ deficiency
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2022 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 6061Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2022
National Category
Natural Sciences
Identifiers
urn:nbn:se:umu:diva-215005 (URN)10.1038/s41467-022-33641-x (DOI)000868657300021 ()36229432 (PubMedID)2-s2.0-85139810931 (Scopus ID)
Available from: 2023-10-05 Created: 2023-10-05 Last updated: 2023-10-09Bibliographically approved
Peselj, C., Ebrahimi, M., Broeskamp, F., Prokisch, S., Habernig, L., Alvarez-Guerra, I., . . . Büttner, S. (2022). Sterol metabolism differentially contributes to maintenance and exit of quiescence. Frontiers in Cell and Developmental Biology, 10, Article ID 788472.
Open this publication in new window or tab >>Sterol metabolism differentially contributes to maintenance and exit of quiescence
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2022 (English)In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 10, article id 788472Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2022
Keywords
lipid droplets, membrane contact sites, NVJ, yeast, quiescence, lipophagy, sterol ester, sterols
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-215006 (URN)10.3389/fcell.2022.788472 (DOI)000761993600001 ()35237594 (PubMedID)2-s2.0-85125340822 (Scopus ID)
Funder
Swedish Research Council, 2015-05468Knut and Alice Wallenberg Foundation, 2017.009Olle Engkvists stiftelse, 194-0681German Research Foundation (DFG), 390939984Olle Engkvists stiftelse, 207-0527German Research Foundation (DFG), 403222702German Research Foundation (DFG), 423813989Swedish Research Council, 2019-05249
Available from: 2023-10-05 Created: 2023-10-05 Last updated: 2023-10-09Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-1241-162x

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