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Publications (10 of 39) Show all publications
Schweingruber, C., Nijssen, J., Mechtersheimer, J., Reber, S., Lebœuf, M., O’Brien, N. L., . . . Hedlund, E. (2025). Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS. Nature Communications, 16, Article ID 4633.
Open this publication in new window or tab >>Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS
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2025 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 16, article id 4633Article in journal (Refereed) Published
Abstract [en]

Mutations in FUS and TARDBP cause amyotrophic lateral sclerosis (ALS), but the precise mechanisms of selective motor neuron degeneration remain unresolved. To address if pathomechanisms are shared across mutations and related to either gain- or loss-of-function, we performed single-cell RNA sequencing across isogenic induced pluripotent stem cell-derived neuron types, harbouring FUS P525L, FUS R495X, TARDBP M337V mutations or FUS knockout. Transcriptional changes were far more pronounced in motor neurons than interneurons. About 20% of uniquely dysregulated motor neuron transcripts were shared across FUS mutations, half from gain-of-function. Most indicated mitochondrial impairments, with attenuated pathways shared with mutant TARDBP M337V as well as C9orf72-ALS patient motor neurons. Mitochondrial motility was impaired in ALS motor axons, even with nuclear localized FUS mutants, demonstrating shared toxic gain-of-function mechanisms across FUS- and TARDBP-ALS, uncoupled from protein mislocalization. These early mitochondrial dysfunctions unique to motor neurons may affect survival and represent therapeutic targets in ALS.

National Category
Cell and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:su:diva-243856 (URN)10.1038/s41467-025-59679-1 (DOI)40389397 (PubMedID)2-s2.0-105005551837 (Scopus ID)
Available from: 2025-06-11 Created: 2025-06-11 Last updated: 2025-06-11Bibliographically approved
Ziqubu, K., Dludla, P. V., Mabhida, S. E., Jack, B. U., Keipert, S., Jastroch, M. & Mazibuko-Mbeje, S. E. (2024). Brown adipose tissue-derived metabolites and their role in regulating metabolism. Metabolism: Clinical and Experimental, 150, Article ID 155709.
Open this publication in new window or tab >>Brown adipose tissue-derived metabolites and their role in regulating metabolism
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2024 (English)In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 150, article id 155709Article, review/survey (Refereed) Published
Abstract [en]

The discovery and rejuvenation of metabolically active brown adipose tissue (BAT) in adult humans have offered a new approach to treat obesity and metabolic diseases. Beyond its accomplished role in adaptive thermogenesis, BAT secretes signaling molecules known as “batokines”, which are instrumental in regulating whole-body metabolism via autocrine, paracrine, and endocrine action. In addition to the intrinsic BAT metabolite-oxidizing activity, the endocrine functions of these molecules may help to explain the association between BAT activity and a healthy systemic metabolic profile. Herein, we review the evidence that underscores the significance of BAT-derived metabolites, especially highlighting their role in controlling physiological and metabolic processes involving thermogenesis, substrate metabolism, and other essential biological processes. The conversation extends to their capacity to enhance energy expenditure and mitigate features of obesity and its related metabolic complications. Thus, metabolites derived from BAT may provide new avenues for the discovery of metabolic health-promoting drugs with far-reaching impacts. This review aims to dissect the complexities of the secretory role of BAT in modulating local and systemic metabolism in metabolic health and disease.

Keywords
Brown adipose tissue, Batokines, Metabolites, Secretome, Metabolism, Obesity, Metabolic diseases
National Category
Cell and Molecular Biology Endocrinology and Diabetes
Identifiers
urn:nbn:se:su:diva-224837 (URN)10.1016/j.metabol.2023.155709 (DOI)001110598400001 ()37866810 (PubMedID)2-s2.0-85175688559 (Scopus ID)
Available from: 2023-12-28 Created: 2023-12-28 Last updated: 2023-12-28Bibliographically approved
Khani, S., Topel, H., Kardinal, R., Tavanez, A. R., Josephrajan, A., Larsen, B. D., . . . Kornfeld, J.-W. (2024). Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function. Nature Metabolism, 6(6), 1053-1075
Open this publication in new window or tab >>Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function
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2024 (English)In: Nature Metabolism, E-ISSN 2522-5812, Vol. 6, no 6, p. 1053-1075Article in journal (Refereed) Published
Abstract [en]

Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function. We identified a cold-inducible promoter that generates a 5′ truncated AC3 mRNA isoform (Adcy3-at), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT). Male mice lacking Adcy3-at display increased energy expenditure and are resistant to obesity and ensuing metabolic imbalances. Mouse and human AC3-AT are retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and lack enzymatic activity. AC3-AT interacts with AC3 and sequesters it in the endoplasmic reticulum, reducing the pool of adenylyl cyclases available for G-protein-mediated cAMP synthesis. Thus, AC3-AT acts as a cold-induced rheostat in BAT, limiting adverse consequences of cAMP activity during chronic BAT activation. 

National Category
Cell and Molecular Biology Endocrinology and Diabetes
Identifiers
urn:nbn:se:su:diva-228971 (URN)10.1038/s42255-024-01033-8 (DOI)001209548100001 ()38684889 (PubMedID)2-s2.0-85191850631 (Scopus ID)
Note

For correction, see Khani, S., Topel, H., Kardinal, R. et al. Publisher Correction: Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function. Nat Metab 7, 855 (2025). https://doi.org/10.1038/s42255-025-01292-z

Available from: 2024-05-14 Created: 2024-05-14 Last updated: 2025-05-27Bibliographically approved
Brunetta, H. S., Jung, A. S., Valdivieso-Rivera, F., de Campos Zani, S. C., Guerra, J., Furino, V. O., . . . Bartelt, A. (2024). IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat. EMBO Journal, 43(21), 4870-4891
Open this publication in new window or tab >>IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat
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2024 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 43, no 21, p. 4870-4891Article in journal (Refereed) Published
Abstract [en]

While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F1Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called “reverse mode” of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.

Keywords
Adipocytes, Metabolism, Mitochondria, Thermogenesis, UCP1
National Category
Molecular Biology
Identifiers
urn:nbn:se:su:diva-239103 (URN)10.1038/s44318-024-00215-0 (DOI)001314227200009 ()39284909 (PubMedID)2-s2.0-85204009117 (Scopus ID)
Available from: 2025-02-07 Created: 2025-02-07 Last updated: 2025-02-07Bibliographically approved
Neuß, T., Chen, M.-C., Wirges, N., Usluer, S., Oellinger, R., Lier, S., . . . Schmid, R. M. (2024). Metabolic Reprogramming Is an Initial Step in Pancreatic Carcinogenesis That Can Be Targeted to Inhibit Acinar-to- Ductal Metaplasia. Cancer Research, 84(14), 2297-2312
Open this publication in new window or tab >>Metabolic Reprogramming Is an Initial Step in Pancreatic Carcinogenesis That Can Be Targeted to Inhibit Acinar-to- Ductal Metaplasia
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2024 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 84, no 14, p. 2297-2312Article in journal (Refereed) Published
Abstract [en]

Metabolic reprogramming is a hallmark of cancer and is crucial for cancer progression, making it an attractive therapeutic target. Understanding the role of metabolic reprogramming in cancer initiation could help identify prevention strategies. To address this, we investigated metabolism during acinar-to-ductal metaplasia (ADM), the first step of pancreatic carcinogenesis. Glycolytic markers were elevated in ADM lesions compared with normal tissue from human samples. Comprehensive metabolic assessment in three mouse models with pancreas-specific activation of KRAS, PI3K, or MEK1 using Seahorse measurements, nuclear magnetic resonance metabolome analysis, mass spectrometry, isotope tracing, and RNA sequencing analysis revealed a switch from oxidative phosphorylation to glycolysis in ADM. Blocking the metabolic switch attenuated ADM formation. Furthermore, mitochondrial metabolism was required for de novo synthesis of serine and glutathione (GSH) but not for ATP production. MYC mediated the increase in GSH intermediates in ADM, and inhibition of GSH synthesis suppressed ADM development. This study thus identifies metabolic changes and vulnerabilities in the early stages of pancreatic carcinogenesis.

National Category
Biochemistry Molecular Biology
Identifiers
urn:nbn:se:su:diva-238295 (URN)10.1158/0008-5472.CAN-23-2213 (DOI)39005053 (PubMedID)2-s2.0-85198592456 (Scopus ID)
Available from: 2025-01-24 Created: 2025-01-24 Last updated: 2025-02-20Bibliographically approved
Gaudry, M. J., Khudyakov, J., Pirard, L., Debier, C., Crocker, D., Crichton, P. G. & Jastroch, M. (2024). Terrestrial Birth and Body Size Tune UCP1 Functionality in Seals. Molecular biology and evolution, 41(4), Article ID msae075.
Open this publication in new window or tab >>Terrestrial Birth and Body Size Tune UCP1 Functionality in Seals
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2024 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 41, no 4, article id msae075Article in journal (Refereed) Published
Abstract [en]

The molecular evolution of the mammalian heater protein UCP1 is a powerful biomarker to understand thermoregulatory strategies during species radiation into extreme climates, such as aquatic life with high thermal conductivity. While fully aquatic mammals lost UCP1, most semiaquatic seals display intact UCP1 genes, apart from large elephant seals. Here, we show that UCP1 thermogenic activity of the small-bodied harbor seal is equally potent compared to terrestrial orthologs, emphasizing its importance for neonatal survival on land. In contrast, elephant seal UCP1 does not display thermogenic activity, not even when translating a repaired or a recently highlighted truncated version. Thus, the thermogenic benefits for neonatal survival during terrestrial birth in semiaquatic pinnipeds maintained evolutionary selection pressure on UCP1 function and were only outweighed by extreme body sizes among elephant seals, fully eliminating UCP1-dependent thermogenesis.

Keywords
UCP1, brown adipose tissue, nonshivering thermogenesis, pseudogene, pinniped
National Category
Evolutionary Biology
Identifiers
urn:nbn:se:su:diva-229018 (URN)10.1093/molbev/msae075 (DOI)001208491100001 ()38606905 (PubMedID)2-s2.0-85191817451 (Scopus ID)
Available from: 2024-05-07 Created: 2024-05-07 Last updated: 2024-11-13Bibliographically approved
Keipert, S., Gaudry, M. J., Kutschke, M., Keuper, M., Dela Rosa, M. A. S., Cheng, Y., . . . Jastroch, M. (2024). Two-stage evolution of mammalian adipose tissue thermogenesis. Science, 384(6700), 1111-1117
Open this publication in new window or tab >>Two-stage evolution of mammalian adipose tissue thermogenesis
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2024 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 384, no 6700, p. 1111-1117Article in journal (Refereed) Published
Abstract [en]

Brown adipose tissue (BAT) is a heater organ that expresses thermogenic uncoupling protein 1 (UCP1) to maintain high body temperatures during cold stress. BAT thermogenesis is considered an overarching mammalian trait, but its evolutionary origin is unknown. We show that adipose tissue of marsupials, which diverged from eutherian mammals ~150 million years ago, expresses a nonthermogenic UCP1 variant governed by a partial transcriptomic BAT signature similar to that found in eutherian beige adipose tissue. We found that the reconstructed UCP1 sequence of the common eutherian ancestor displayed typical thermogenic activity, whereas therian ancestor UCP1 is nonthermogenic. Thus, mammalian adipose tissue thermogenesis may have evolved in two distinct stages, with a prethermogenic stage in the common therian ancestor linking UCP1 expression to adipose tissue and thermal stress. We propose that in a second stage, UCP1 acquired its thermogenic function specifically in eutherians, such that the onset of mammalian BAT thermogenesis occurred only after the divergence from marsupials. 

National Category
Evolutionary Biology
Identifiers
urn:nbn:se:su:diva-231101 (URN)10.1126/science.adg1947 (DOI)38843333 (PubMedID)2-s2.0-85195438772 (Scopus ID)
Available from: 2024-06-17 Created: 2024-06-17 Last updated: 2024-06-17Bibliographically approved
Schmidt, S., Stautner, C., Vu, D. T., Heinz, A., Regensburger, M., Karayel, O., . . . Wurst, W. (2023). A reversible state of hypometabolism in a human cellular model of sporadic Parkinson's disease. Nature Communications, 14(1), Article ID 7674.
Open this publication in new window or tab >>A reversible state of hypometabolism in a human cellular model of sporadic Parkinson's disease
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 7674Article in journal (Refereed) Published
Abstract [en]

Sporadic Parkinson's Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis based on transcriptomics, proteomics, and metabolomics identified the citric acid cycle, specifically the alpha-ketoglutarate dehydrogenase complex (OGDHC), as bottleneck in sPD metabolism. A follow-up study of the patients approximately 10 years after initial biopsy demonstrated a correlation between OGDHC activity in our cellular model and the disease progression. In addition, the alterations in cellular metabolism observed in our cellular model were restored by interfering with the enhanced SHH signal transduction in sPD. Thus, inhibiting overactive SHH signaling may have potential as neuroprotective therapy during early stages of sPD. Mitochondrial dysfunction is a contributing factor in Parkinson's disease. Here the authors carry out a multilayered omics analysis of Parkinson's disease patient-derived neuronal cells, which reveals a reversible hypometabolism mediated by alpha-ketoglutarate dehydrogenase deficiency, which is correlated with disease progression in the donating patients.

National Category
Neurosciences
Identifiers
urn:nbn:se:su:diva-225819 (URN)10.1038/s41467-023-42862-7 (DOI)001110180200003 ()37996418 (PubMedID)2-s2.0-85177734756 (Scopus ID)
Available from: 2024-01-23 Created: 2024-01-23 Last updated: 2024-01-23Bibliographically approved
Herrnhold, M., Hamp, I., Plettenburg, O., Jastroch, M. & Keuper, M. (2023). Adverse bioenergetic effects of N-acyl amino acids in human adipocytes overshadow beneficial mitochondrial uncoupling. Redox Biology, 66, Article ID 102874.
Open this publication in new window or tab >>Adverse bioenergetic effects of N-acyl amino acids in human adipocytes overshadow beneficial mitochondrial uncoupling
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2023 (English)In: Redox Biology, E-ISSN 2213-2317, Vol. 66, article id 102874Article in journal (Refereed) Published
Abstract [en]

Objective: Enhancing energy turnover via uncoupled mitochondrial respiration in adipose tissue has great potential to improve human obesity and other metabolic complications. However, the amount of human brown adipose tissue and its uncoupling protein 1 (UCP1) is low in obese patients. Recently, a class of endogenous molecules, N-acyl amino acids (NAAs), was identified as mitochondrial uncouplers in murine adipocytes, presumably acting via the adenine nucleotide translocator (ANT). Given the translational potential, we investigated the bioenergetic effects of NAAs in human adipocytes, characterizing beneficial and adverse effects, dose ranges, amino acid derivatives and underlying mechanisms.

Method: NAAs with neutral (phenylalanine, leucine, isoleucine) and polar (lysine) residues were synthetized and assessed in intact and permeabilized human adipocytes using plate-based respirometry. The Seahorse technology was applied to measure bioenergetic parameters, dose-dependency, interference with UCP1 and adenine nucleotide translocase (ANT) activity, as well as differences to the established chemical uncouplers niclosamide ethanolamine (NEN) and 2,4-dinitrophenol (DNP).

Result: NAAs with neutral amino acid residues potently induce uncoupled respiration in human adipocytes in a dose-dependent manner, even in the presence of the UCP1-inhibitor guanosine diphosphate (GDP) and the ANT-inhibitor carboxyatractylate (CAT). However, neutral NAAs significantly reduce maximal oxidation rates, mitochondrial ATP-production, coupling efficiency and reduce adipocyte viability at concentrations above 25 μM. The in vitro therapeutic index (using induced proton leak and viability as determinants) of NAAs is lower than that of NEN and DNP.

Conclusion: NAAs are potent mitochondrial uncouplers in human adipocytes, independent of UCP1 and ANT. However, previously unnoticed adverse effects harm adipocyte functionality, reduce the therapeutic index of NAAs in vitro and therefore question their suitability as anti-obesity agents without further chemical modifications.

Keywords
Obesity, Metabolism, Mitochondria, UCP1, Adipocytes, Uncoupling
National Category
Biochemistry Molecular Biology Nutrition and Dietetics
Identifiers
urn:nbn:se:su:diva-223932 (URN)10.1016/j.redox.2023.102874 (DOI)001076198300001 ()37683300 (PubMedID)2-s2.0-85169887542 (Scopus ID)
Available from: 2023-11-29 Created: 2023-11-29 Last updated: 2025-02-20Bibliographically approved
Jastroch, M. & van Breukelen, F. (2023). Hypometabolism with the speed of ultrasound [Letter to the editor]. Nature Metabolism, 5(5), 722-723
Open this publication in new window or tab >>Hypometabolism with the speed of ultrasound
2023 (English)In: Nature Metabolism, E-ISSN 2522-5812, Vol. 5, no 5, p. 722-723Article in journal, Letter (Refereed) Published
Abstract [en]

How mammals enter hypometabolic states, known as torpor and hibernation, has fascinated researchers for decades, but the central control mechanisms that regulate entry into torpor have surfaced only recently. Yang and colleagues demonstrate that torpor-like hypometabolic states can be induced non-invasively by ultrasound, providing new routes for exploiting the underlying mechanisms and biomedical applications of this process in the future.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:su:diva-234681 (URN)10.1038/s42255-023-00795-x (DOI)000994766800002 ()37231249 (PubMedID)2-s2.0-85160301162 (Scopus ID)
Available from: 2024-10-23 Created: 2024-10-23 Last updated: 2024-10-23Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0358-3865

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