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- Hällberg, B Martin, et al.
(author)
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Making proteins in the powerhouse
- 2014
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In: Cell Metabolism. - Stockholm : Karolinska Institutet, Dept of Cell and Molecular Biology. - 1550-4131 .- 1932-7420.
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Journal article (peer-reviewed)abstract
- Understanding regulation of mitochondrial DNA (mtDNA) expression is of considerable interest as mitochondrial dysfunction is important in human pathology and ageing. Similar to the situation in bacteria, there is no compartmentalization between transcription and translation in mitochondria; hence, both processes are likely to have a direct molecular crosstalk. Accumulating evidence suggests that there are important mechanisms for regulation of mammalian mtDNA expression at the posttranscriptional level. Regulation of mRNA maturation, mRNA stability, translational coordination, ribosomal biogenesis and translation itself, all form the basis for controlling oxidative phosphorylation capacity. Consequently, a wide variety of inherited human mitochondrial diseases are caused by mutations of nuclear genes regulating various aspects of mitochondrial translation. Furthermore, mutations of mtDNA, associated with human disease and ageing, often affect tRNA genes critical for mitochondrial translation. Recent advances in molecular understanding of mitochondrial translation regulation will likely provide novel avenues for modulating mitochondrial function to treat human disease.
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- Baeckdahl, Jesper, et al.
(author)
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Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin
- 2021
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 33:9, s. 1869-
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Journal article (peer-reviewed)abstract
- The contribution of cellular heterogeneity and architecture to white adipose tissue (WAT) function is poorly understood. Herein, we combined spatially resolved transcriptional profiling with single-cell RNA sequencing and image analyses to map human WAT composition and structure. This identified 18 cell classes with unique propensities to form spatially organized homo-and heterotypic clusters. Of these, three constituted mature adipocytes that were similar in size, but distinct in their spatial arrangements and transcriptional profiles. Based on marker genes, we termed these Adipo(LEP), Adipo(PLIN), and Adipo(SAA). We confirmed, in independent datasets, that their respective gene profiles associated differently with both adipocyte and whole-body insulin sensitivity. Corroborating our observations, insulin stimulation in vivo by hyperinsulinemic-euglycemic clamp showed that only Adipo(PLIN) displayed a transcriptional response to insulin. Altogether, by mining this multimodal resource we identify that human WAT is composed of three classes of mature adipocytes, only one of which is insulin responsive.
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| 10. |
- Balaz, M., et al.
(author)
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Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation
- 2019
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 29:4
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Journal article (peer-reviewed)abstract
- Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism.
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