| 1. |
- Eisenberg, Tobias, et al.
(författare)
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Cardioprotection and lifespan extension by the natural polyamine spermidine
- 2016
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 22:12, s. 1428-1438
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Tidskriftsartikel (refereegranskat)abstract
- Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.
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| 2. |
- Gross, Angelina S., et al.
(författare)
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Acetyl-CoA carboxylase 1-dependent lipogenesis promotes autophagy downstream of AMPK
- 2019
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 294:32, s. 12020-12039
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Tidskriftsartikel (refereegranskat)abstract
- 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 (acc1(S/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, acc1(S/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 acc1(S/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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| 3. |
- Gross, Angelina S., et al.
(författare)
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Acetyl-CoA carboxylase 1–dependent lipogenesis promotes autophagy downstream of AMPK
- 2019
-
Ingår i: Journal of Biological Chemistry. - : Elsevier. - 0021-9258 .- 1083-351X. ; 294:32, s. 12020-12039
-
Tidskriftsartikel (refereegranskat)abstract
- 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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| 4. |
- Andréasson, Claes, et al.
(författare)
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Mitochondria orchestrate proteostatic and metabolic stress responses
- 2019
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Ingår i: EMBO Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 20:10
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Tidskriftsartikel (refereegranskat)abstract
- The eukaryotic cell is morphologically and functionally organized as an interconnected network of organelles that responds to stress and aging. Organelles communicate via dedicated signal transduction pathways and the transfer of information in form of metabolites and energy levels. Recent data suggest that the communication between organellar proteostasis systems is a cornerstone of cellular stress responses in eukaryotic cells. Here, we discuss the integration of proteostasis and energy fluxes in the regulation of cellular stress and aging. We emphasize the molecular architecture of the regulatory transcriptional pathways that both sense and control metabolism and proteostasis. A special focus is placed on mechanistic insights gained from the model organism budding yeast in signaling from mitochondria to the nucleus and how this shapes cellular fitness.
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| 5. |
- Aufschnaiter, Andreas, Dr. rer. nat. 1988-, et al.
(författare)
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Peroxisomal fission controls yeast life span
- 2015
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Ingår i: Cell Cycle. - : Taylor & Francis. - 1538-4101 .- 1551-4005. ; 14:15, s. 2389-2390
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Tidskriftsartikel (refereegranskat)
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| 6. |
- Aufschnaiter, Andreas, et al.
(författare)
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Taking out the garbage : cathepsin D and calcineurin in neurodegeneration
- 2017
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Ingår i: Neural Regeneration Research. - : Medknow. - 1673-5374 .- 1876-7958. ; 12:11, s. 1776-1779
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Forskningsöversikt (refereegranskat)abstract
- 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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| 7. |
- Aufschnaiter, Andreas, et al.
(författare)
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The Coordinated Action of Calcineurin and Cathepsin D Protects Against alpha-Synuclein Toxicity
- 2017
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Ingår i: Frontiers in Molecular Neuroscience. - : Frontiers Media SA. - 1662-5099. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The degeneration of dopaminergic neurons during Parkinson's disease (PD) is intimately linked to malfunction of alpha-synuclein (alpha Syn), the main component of the proteinaceous intracellular inclusions characteristic for this pathology. The cytotoxicity of alpha Syn 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 alpha Syn 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 alpha Syn 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 alpha Syn cytotoxicity.
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| 8. |
- Berndtsson, Jens, et al.
(författare)
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Respiratory supercomplexes enhance electron transport by decreasing cytochrome c diffusion distance
- 2020
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Ingår i: Embo Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- 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 cytochromec 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 cytochromec. 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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| 9. |
- Carmona-Gutierrez, D., et al.
(författare)
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Guidelines and recommendations on yeast cell death nomenclature
- 2018
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Ingår i: Microbial Cell. - : Shared Science Publishers OG. - 2311-2638. ; 5:1, s. 4-31
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Forskningsöversikt (refereegranskat)abstract
- Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cellular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the definition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differential definition of terms including apoptosis, regulated necrosis, and autophagic cell death, as we refer to additional cell death routines that are relevant for the biology of (at least some species of) yeast. As this area of investigation advances rapidly, changes and extensions to this set of recommendations will be implemented in the years to come. Nonetheless, we strongly encourage the authors, reviewers and editors of scientific articles to adopt these collective standards in order to establish an accurate framework for yeast cell death research and, ultimately, to accelerate the progress of this vibrant field of research.
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| 10. |
- Cavinato, Maria, et al.
(författare)
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Targeting cellular senescence based on interorganelle communication, multilevel proteostasis, and metabolic control
- 2021
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 228:12, s. 3834-3854
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Forskningsöversikt (refereegranskat)abstract
- Cellular senescence, a stable cell division arrest caused by severe damage and stress, is a hallmark of aging in vertebrates including humans. With progressing age, senescent cells accumulate in a variety of mammalian tissues, where they contribute to tissue aging, identifying cellular senescence as a major target to delay or prevent aging. There is an increasing demand for the discovery of new classes of small molecules that would either avoid or postpone cellular senescence by selectively eliminating senescent cells from the body (i.e., 'senolytics') or inactivating/switching damage-inducing properties of senescent cells (i.e., 'senostatics/senomorphics'), such as the senescence-associated secretory phenotype. Whereas compounds with senolytic or senostatic activity have already been described, their efficacy and specificity has not been fully established for clinical use yet. Here, we review mechanisms of senescence that are related to mitochondria and their interorganelle communication, and the involvement of proteostasis networks and metabolic control in the senescent phenotype. These cellular functions are associated with cellular senescence in in vitro and in vivo models but have not been fully exploited for the search of new compounds to counteract senescence yet. Therefore, we explore possibilities to target these mechanisms as new opportunities to selectively eliminate and/or disable senescent cells with the aim of tissue rejuvenation. We assume that this research will provide new compounds from the chemical space which act as mimetics of caloric restriction, modulators of calcium signaling and mitochondrial physiology, or as proteostasis optimizers, bearing the potential to counteract cellular senescence, thereby allowing healthy aging.
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| 11. |
- Charmpilas, Nikolaos, et al.
(författare)
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Acyl-CoA-binding protein (ACBP) : a phylogenetically conserved appetite stimulator
- 2020
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Ingår i: Cell Death and Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Recently, we reported that, in mice, hunger causes the autophagy-dependent release of a protein called acyl-CoA-binding protein or diazepam binding inhibitor (ACBP/DBI) from cells, resulting in an increase in plasma ACBP concentrations. Administration of extra ACBP is orexigenic and obesogenic, while its neutralization is anorexigenic in mice, suggesting that ACBP is a major stimulator of appetite and lipo-anabolism. Accordingly, obese persons have higher circulating ACBP levels than lean individuals, and anorexia nervosa is associated with subnormal ACBP plasma concentrations. Here, we investigated whether ACBP might play a phylogenetically conserved role in appetite stimulation. We found that extracellular ACBP favors sporulation in Saccharomyces cerevisiae, knowing that sporulation is a strategy for yeast to seek new food sources. Moreover, in the nematode Caenorhabditis elegans, ACBP increased the ingestion of bacteria as well as the frequency pharyngeal pumping. These observations indicate that ACBP has a phylogenetically ancient role as a 'hunger factor' that favors food intake.
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| 12. |
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| 13. |
- 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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| 14. |
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| 15. |
- Diessl, Jutta, 1989-
(författare)
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Metal homeostasis as critical determinant for cellular fitness
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Metals play a crucial role in cellular biology. Bulk and trace metals such as calcium and manganese regulate a plethora of cellular processes ranging from signaling and oxidative stress to proteostasis and energy metabolism. Fine-tuning metal levels and distribution safeguards all forms of life from compromised cellular fitness and cell death elicited by metal deficiency or overload. However, the underlying molecular mechanisms eventually leading to cellular demise remain elusive. In this thesis, we studied the fundamental impact of disrupted metal homeostasis on cellular survival focusing on mitochondrial and lysosomal processes in Saccharomyces cerevisiae and Drosophila melanogaster. In Paper I, we establish Coenzyme Q (CoQ) biosynthesis in mitochondria as the prime target of cellular manganese overload and propose a molecular mechanism underlying manganese toxicity. Combining proteomics, genome-wide screening and comprehensive metal analyses, we identify mismetallation of the di-iron hydroxylase Coq7, an enzyme of CoQ biosynthesis, as cause for the CoQ deficiency upon manganese overload. Overexpression of Coq7 not only restored CoQ-mediated electron transport through the respiratory chain but also prevented age-associated death. Expanding from trace to bulk metals, we further assessed the impact of disrupted calcium and manganese homeostasis on cellular survival. In Paper II, we created a fluorescence-based reporter system for the Ca2+/calmodulin-dependent phosphatase calcineurin, a nexus for cell stress-induced signaling. Combining our reporters with a live/dead staining allows for quantification of acute and chronic changes in calcium signaling in living, unperturbed cells. In Paper III, we elucidate the impact of nutritional regimes known to improve cellular survival on cells compromised in the handling of calcium and manganese due to the absence of Pmr1, a Ca2+/Mn2+ ATPase of the secretory pathway. We demonstrate that caloric restriction prevents manganese-induced disruption of mitochondrial energy metabolism and improves survival independent of calcineurin activity and CoQ biosynthesis. In Papers IV and V, we studied the interplay of metal levels and calcium signaling in the context of neurodegeneration and report that calcineurin stimulates lysosomal proteolysis, thereby preventing proteotoxicity in yeast and Drosophila models for Parkinson’s disease. Collectively, our results provide new insights into the consequences of disrupted metal homeostasis for cellular fitness and unravel a novel link between manganese overload, mitochondrial bioenergetics and CoQ biosynthesis conserved across species.
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| 16. |
- Diessl, Jutta, et al.
(författare)
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Stable and destabilized GFP reporters to monitor calcineurin activity in Saccharomyces cerevisiae
- 2020
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Ingår i: Microbial cell. - : Shared Science Publishers OG. - 2311-2638. ; 7:4, s. 106-114
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Tidskriftsartikel (refereegranskat)abstract
- The protein phosphatase calcineurin is activated in response to rising intracellular Ca2+ levels and impacts fundamental cellular processes in organisms ranging from yeast to humans. In fungi, calcineurin orchestrates cellular adaptation to diverse environmental challenges and is essential for virulence of pathogenic species. To enable rapid and large-scale assessment of calcineurin activity in living, unperturbed yeast cells, we have generated stable and destabilized GFP transcriptional reporters under the control of a calcineurin-dependent response element (CDRE). Using the reporters, we show that the rapid dynamics of calcineurin activation and deactivation can be followed by flow cytometry and fluorescence microscopy. This system is compatible with live/dead staining that excludes confounding dead cells from the analysis. The reporters provide technology to monitor calcineurin dynamics during stress and ageing and may serve as a drug-screening platform to identify novel antifungal compounds that selectively target calcineurin.
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| 17. |
- Duan, Jianli, et al.
(författare)
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Bab2 Functions as an Ecdysone-Responsive Transcriptional Repressor during Drosophila Development
- 2020
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 32:4
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Tidskriftsartikel (refereegranskat)abstract
- Drosophila development is governed by distinct ecdysone steroid pulses that initiate spatially and temporally defined gene expression programs. The translation of these signals into tissue-specific responses is crucial for metamorphosis, but the mechanisms that confer specificity to systemic ecdysone pulses are far from understood. Here, we identify Bric-a-brac 2 (Bab2) as an ecdysone-responsive transcriptional repressor that controls temporal gene expression during larval to pupal transition. Bab2 is necessary to terminate Salivary gland secretion (Sgs) gene expression, while premature Bab2 expression blocks Sgs genes and causes precocious salivary gland histolysis. The timely expression of bab2 is controlled by the ecdysone-responsive transcription factor Broad, and manipulation of EcR/USP/Broad signaling induces inappropriate Bab2 expression and termination of Sgs gene expression. Bab2 directly binds to Sgs loci in vitro and represses all Sgs genes in vivo. Our work characterizes Bab2 as a temporal regulator of somatic gene expression in response to systemic ecdysone signaling.
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| 18. |
- Ebrahimi, Mahsa, 1985-
(författare)
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Cellular remodeling in response to nutrient exhaustion : From membrane contact sites to autophagy
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Adaptation to fluctuating environments is critical for cellular fitness and survival. Cells need to sense changes in their surroundings and quickly adjust cellular homeostasis and metabolism accordingly. Diverse sensing and signaling pathways govern the cellular responses to extracellular cues, enabling for instance adaptation to changes in nutrient availability. Eukaryotic cells have evolved complex regulatory networks to deal with variable nutrient supply, and most of these evolutionary conserved nutrient signaling pathways are intimately linked to aging and age-associated diseases. Despite significant advances, the adaptation to environmental changes through nutrient signaling pathways and the impact of these pathways on a cell’s lifespan remain incompletely understood. This thesis focuses on the molecular mechanisms by which nutrient depletion affects cellular remodeling and lifespan of the budding yeast Saccharomyces cerevisiae. In paper I, we elucidate the impact of nutritional regimes on cellular survival during aging, with a particular focus on phosphate restriction. We show that phosphate restriction results in an activation of autophagy, the main cellular bulk degradation process, and a prominent extension of lifespan. Our results indicate that longevity induced by phosphate restriction relies on the sequential and coordinated function of autophagy and the multivesicular body pathway, a catabolic process critical for the degradation of plasma membrane components. In addition, we find the nutrient-responsive kinase Pho85 to be essential for autophagy induction and cellular fitness upon phosphate restriction. In paper II, we illustrate how nutrition limitation affects interorganellar communication as well as lipid droplet biogenesis, subcellular organization and utilization. We demonstrate that phosphate depletion induces the remodeling and expansion of the contacts between the perinuclear ER and the vacuole, the so-called nucleus-vacuole junctions. Moreover, we show that the biosynthesis of sterol esters, which are stored in lipid droplets upon nutrient depletion, is essential for survival upon phosphate but not glucose exhaustion. In paper III, we identify Snd3 as novel component of the nucleus-vacuole junctions, critical for membrane contact site formation and dynamic remodeling upon glucose exhaustion. Additionally, we show that the regulatory function of Snd3 is governed by central glucose signaling pathways. Taken together, our studies advance our understanding of how nutritional regimes and signaling pathways impact on cellular remodeling and survival during aging.
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| 19. |
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| 20. |
- Ebrahimi, Mahsa, 1985-, et al.
(författare)
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Phosphate Restriction Promotes Longevity via Activation of Autophagy and the Multivesicular Body Pathway
- 2021
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 21. |
- 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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| 22. |
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| 23. |
- Habernig, Lukas, et al.
(författare)
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Ca2+ administration prevents α-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
-
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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| 24. |
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| 25. |
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