| 1. |
- Diessl, Jutta, 1989-, et al.
(författare)
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Manganese-driven CoQ deficiency
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- 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. Across phylae, excess manganese disrupts energy metabolism by unclear mechanisms. Here, Diessl et al. report that failure of mitochondrial bioenergetics upon manganese overload is due to mismetallation of a diiron enzyme crucial for CoQ biosynthesis
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| 2. |
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| 3. |
- Habernig, Lukas, et al.
(författare)
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Ca2+ administration prevents alpha-synuclein proteotoxicity by stimulating calcineurin-dependent lysosomal proteolysis
- 2021
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:11
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 4. |
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| 5. |
- Habernig, Lukas, et al.
(författare)
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Ca2+ administration prevents α-synuclein proteotoxicity by stimulating calcineurin-dependent lysosomal proteolysis
- 2021
-
Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:11
-
Tidskriftsartikel (refereegranskat)abstract
- 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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| 6. |
- Kohler, Andreas, Dr. rer. nat. 1988-, et al.
(författare)
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Mitochondrial lipids in neurodegeneration
- 2016
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Ingår i: Cell and Tissue Research. - : Springer. - 0302-766X .- 1432-0878. ; 367:1, s. 125-140
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- 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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| 7. |
- Peselj, Carlotta, 1990-
(författare)
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Interorganellar connectivity : From protein to lipid homeostasis
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Interorganellar connectivity is fundamental for the maintenance of organellar and cellular functionality and viability. This is achieved and maintained by a complex network of signaling cascades, vesicle trafficking between organelles as well as by establishment of direct physical contact at membrane contact sites (MCS). These MCS are sites of close proximity between different organelles, formed by dedicated tethering machineries, that exist between virtually all organelles within a eukaryotic cell. MCS change in size, abundance and molecular architecture in response to metabolic cues and serve to exchange lipids, metabolites and ions. The nucleus-vacuolar junctions (NVJs), establishing contact between the perinuclear ER and the vacuole in yeast, also serve as platform for the biogenesis of a subpopulation of lipid droplets (LD), organelles that function as storage for neutral lipids and contribute to the detoxification of possibly harmful lipid species and aggregated proteins. While it is clear that interorganellar communication at MCS affects cellular functionality at multiple levels, we are just beginning to understand their contribution to cellular protein and lipid homeostasis and their dynamic remodeling in response to metabolic or proteostatic challenges. In Paper I, we identify a novel regulator and component of NVJs, which is essential for contact site formation as well as their expansion in response to glucose exhaustion, controlled by central glucose signaling pathways. In Paper II, we further characterize the role of this protein in ER protein homeostasis and establish it as a transmembrane chaperone that supports the biogenesis of a subset of ER transmembrane proteins, including Nvj1, the main tether of the NVJs, and several enzymes critical for lipid metabolism. Lack of this chaperone leads to aggregation and premature degradation of its substrates, resulting in severe proteostatic and lipid bilayer stress. In Paper III, we investigate the impact of different nutritional regimes on LD biogenesis, subcellular organization and utilization. While the LD subpopulation synthesized at and clustered around the NVJs seems dispensable for long-term survival, we find that a general increase in the synthesis of neutral lipids to be stored in LDs is essential to sustain viability in phosphate-restricted conditions and supports regrowth when de novo fatty acid synthesis is blocked. In Paper IV, we address interorganellar communication between the mitochondria and the nucleus, showing how mitochondrial translation accuracy modulates nuclear gene expression and affects cytosolic protein homeostasis as well as cellular survival during aging. Collectively, these studies provide new insights into different aspects of organellar communication and their impact on cellular fitness.
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| 8. |
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| 9. |
- Peselj, Carlotta, 1990-, et al.
(författare)
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Sterol Metabolism Differentially Contributes to Maintenance and Exit of Quiescence
- 2022
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Nutrient starvation initiates cell cycle exit and entry into quiescence, a reversible, non-proliferative state characterized by stress tolerance, longevity and large-scale remodeling of subcellular structures. Depending on the nature of the depleted nutrient, yeast cells are assumed to enter heterogeneous quiescent states with unique but mostly unexplored characteristics. Here, we show that storage and consumption of neutral lipids in lipid droplets (LDs) differentially impacts the regulation of quiescence driven by glucose or phosphate starvation. Upon prolonged glucose exhaustion, LDs were degraded in the vacuole via Atg1-dependent lipophagy. In contrast, yeast cells entering quiescence due to phosphate exhaustion massively over-accumulated LDs that clustered at the vacuolar surface but were not engulfed via lipophagy. Excessive LD biogenesis required contact formation between the endoplasmic reticulum and the vacuole at nucleus-vacuole junctions and was accompanied by a shift of the cellular lipid profile from membrane towards storage lipids, driven by a transcriptional upregulation of enzymes generating neutral lipids, in particular sterol esters. Importantly, sterol ester biogenesis was critical for long-term survival of phosphate-exhausted cells and supported rapid quiescence exit upon nutrient replenishment, but was dispensable for survival and regrowth of glucose-exhausted cells. Instead, these cells relied on de novo synthesis of sterols and fatty acids for quiescence exit and regrowth. Phosphate-exhausted cells efficiently mobilized storage lipids to support several rounds of cell division even in presence of inhibitors of fatty acid and sterol biosynthesis. In sum, our results show that neutral lipid biosynthesis and mobilization to support quiescence maintenance and exit is tailored to the respective nutrient scarcity.
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| 10. |
- Suhm, Tamara, et al.
(författare)
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Mitochondrial Translation Efficiency Controls Cytoplasmic Protein Homeostasis
- 2018
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 27:6
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Tidskriftsartikel (refereegranskat)abstract
- Cellular proteostasis ismaintained via the coordinated synthesis, maintenance, and breakdown of proteins in the cytosol and organelles. While biogenesis of the mitochondrial membrane complexes that execute oxidative phosphorylation depends on cytoplasmic translation, it is unknown how translation within mitochondria impacts cytoplasmic proteostasis and nuclear gene expression. Here we have analyzed the effects of mutations in the highly conserved accuracy center of the yeast mitoribosome. Decreased accuracy of mitochondrial translation shortened chronological lifespan, impaired management of cytosolic protein aggregates, and elicited a general transcriptional stress response. In striking contrast, increased accuracy extended lifespan, improved cytosolic aggregate clearance, and suppressed a normally stress-induced, Msn2/4-dependent interor-ganellar proteostasis transcription program (IPTP) that regulates genes important for mitochondrial proteostasis. Collectively, the data demonstrate that cytosolic protein homeostasis and nuclear stress signaling are controlled by mitochondrial translation efficiency in an inter-connected organelle quality control network that determines cellular lifespan.
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