Biology subjects

Wedell, A.

Publications and source records attributed to Wedell, A..

5 recordsLinked to original sources

bioRxiv2026

NeuroEnergetics-on-Chip: a novel 3-compartment microfluidic platform to study metabolic interactions between brain parenchyma and cerebral vasculature

Neurological disorders are a major cause of death and disability worldwide. The brains energy metabolism is essential to its proper function, yet the mechanisms driving neuroenergetic dysfunction remain poorly understood. A key challenge is the limited availability of human-relevant models that can reproduce the complexity of brain physiology. An Organ-on-Chip (OoC) system was developed to mimic the neurovascular unit metabolic coupling by incorporating human isogenic iPSC-derived endothelial-like cells, pericyte-like cells, astrocytes, and a cerebral organoid, representing the main cellular components of the NVU. The novel, customized microfluidic platform enables research on neurovascular coupling by interconnecting a blood-brain barrier-on-a-chip model with a 3D brain parenchymal compartment to mimic physiological conditions. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/733618v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@9fc9f3org.highwire.dtl.DTLVardef@838a7corg.highwire.dtl.DTLVardef@1f8df76org.highwire.dtl.DTLVardef@16ef40_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

MitoSAM-dependent lipoylation controls postnatal heart development via metabolic remodeling

The neonatal heart undergoes a rapid metabolic transition from fetal glycolysis to oxidative phosphorylation, requiring coordinated metabolic remodeling. Mechanisms driving this transition remain unclear. Here, we demonstrate that sufficient mitochondrial S-adenosylmethionine (mitoSAM), imported via the solute carrier Slc25a26, is essential for this shift by sustaining the lipoylation of 2-oxoacid dehydrogenases, critical for TCA cycle activation. Proteomic and metabolomic profiling revealed that reduced mitoSAM availability impaired lipoylation, blocking TCA cycle function and restricting nucleotide synthesis, while mitochondrial gene expression and respiratory capacity remained largely intact. In vivo EdU labeling showed persistent cardiomyocyte proliferation imposing further strain on nucleotide pools. Supplementation with medium-chain triglycerides during the suckling-to-weaning transition restored metabolic function and normalized cardiac growth and morphology. Our data reveal a critical developmental window in which mitoSAM-dependent lipoylation ensures heart maturation.

biochemistry↗

bioRxiv2024

The mitochondrial methylation potential gates mitoribosome assembly

S-adenosylmethionine (SAM) is crucial for cellular processes, primarily serving as the principal methyl group donor of the cell and playing a key role in gene regulation and translation on the ribosome. Inside mitochondria, SAM-dependent methylations occur at several steps of gene expression, but their role and significance remain unclear. Using direct long-read RNA sequencing on mouse tissue and mouse embryonic fibroblasts, we demonstrate that the mitochondrial ribosomal gene cluster is not efficiently processed without mitochondrial SAM. This results in the accumulation of unprocessed ribosomal RNA precursors. Protein profiling of ribosome fractions revealed that these precursors are associated with processing and ribosome assembly factors, indicating stalling at an early stage. Structural analysis of the mitochondrial ribosome by cryogenic electron microscopy revealed that mitochondrial SAM is required during peptidyl transferase centre formation and mitochondrial ribosome assembly. Our data thus identify a critical role for methylation at two steps during mitochondrial gene expression.

molecular biology↗

bioRxiv2023

Parkin is not required to sustain OXPHOS function in adult mammalian tissues

Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinsons disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development of Parkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygous PRKN pathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.

cell biology↗

bioRxiv2019

Versatile proteome labelling in fruit flies with SILAF

Drosophila melanogaster has been a working horse of genetics and cell biology for more than a century. However, proteomic-based methods have been limited due to technical obstacles, especially the lack of reliable labelling methods. Here, we advanced a chemically defined food source into stable-isotope labelling of amino acids in flies (SILAF). It allows for the rapid generation of a large number of flies with full incorporation of lysine-6. SILAF followed by fractionation and enrichment gave proteomic insights at a depth of 5,966 proteins and 7,496 phosphorylation sites, which substantiated metabolic regulation on enzymatic level. Furthermore, the label can be traced and predicts protein turnover rates during different developmental stages. The ease and versatility of the method actuates the fruit fly as an appealing model in proteomic and post-translational modification studies and it enlarges potential metabolic applications based on heavy amino acid diets.

molecular biology↗