Biology subjects

Weldemariam, M. M.

Publications and source records attributed to Weldemariam, M. M..

4 recordsLinked to original sources

bioRxiv2026

Dual role of the OMM E3 Ub ligase MARCH5 in de novo peroxisome biogenesis and mitochondrial quality control through direct regulation of Pex26.

Recent evidence indicates that mitochondria, through the activity of the E3 Ub ligase MARCH5, are critical for de novo peroxisome biogenesis. Here we report that peroxisome biogenesis factor Pex26 is a MARCH5 client protein. In peroxisome-containing cells, MARCH5 interacts with Pex26 and facilitates the transfer of newly synthesized Pex26 from the OMM to peroxisomes. MARCH5 also controls peroxisomal delivery of other candidate peroxins in peroxisome-containing cells. On the other hand, in peroxisome-deficient cells, the turnover rate of Pex26 is dramatically increased, and MARCH5 targets this protein for p97-dependent proteasomal degradation. Both activities are mediated by MARCH5-dependent Pex26 ubiquitination. Knockout of Pex26 induces the accumulation of cells containing Tom20-positive, Catalase-deficient pre-peroxisomes. Further supporting the critical role of MARCH5 in peroxisome biogenesis, these structures are absent in Pex26/MARCH5 double knockout cells. The data support the model, where in peroxisome-containing cells, MARCH5 acts as a peroxisome biogenesis factor, while with defective peroxisome biogenesis, as in Zellweger syndrome cells, it protects mitochondria from potentially toxic accumulation of peroxins on the OMM.

cell biology↗

bioRxiv2026

Rubicon modulates neuroimmune responses following traumatic brain injury

Traumatic brain injury (TBI) elicits robust neuroinflammation and oxidative stress, coupled with an acute inhibition of macro-autophagy (autophagy) in neurons and microglia. Rubicon (Rubcn), a Beclin1 interacting protein that suppresses autophagy and mediates LC3-associated phagocytosis and endocytosis (LAP/LANDO), influences inflammatory signaling in metabolic, neurodegenerative, and inflammaging diseases; yet its role in acquired brain injury has not been defined. Using a controlled cortical impact model, we investigated the role of Rubicon in acute neuroinflammatory responses following injury by comparing wild-type and Rubcn-mutant mice. Bulk-RNA sequencing of injured cortex revealed attenuated induction of inflammatory pathways and reduced activation of pro-inflammatory microglial/macrophage phenotype in injured Rubcn-mutant mice. Rubcn-mutant mice demonstrated less pronounced inhibition of autophagy during the acute phase of injury. Although the inflammatory dicerences were transient, Rubicon mutant mice exhibited improved motor coordination and gait stability during recovery. Proteomic analyses revealed the presence of a truncated Rubicon protein in the mutant mice and identified the negative regulator of reactive oxygen species (NRROS) as a novel interactor of Rubicon. Consistent with this interaction, Rubcn-mutant mice displayed markedly reduced oxidative damage, indicated by decreased lipid peroxidation after injury. Together, these findings indicate that Rubicon promotes acute neuroinflammatory and oxidative stress responses following TBI by modulating autophagy and ROS production. Rubicon mediated pathways may serve as therapeutic targets that ocer a neuroprotective strategy to improve outcomes after TBI.

neuroscience↗

bioRxiv2025

Lysosomal multi-omics reveals altered sphingolipid catabolism as driver of lysosomal dysfunction in the aging brain.

Recent data indicate that lipid composition has profound influence on the brain function and that changes in lipid homeostasis affect brain aging and predisposition to neurodegenerative diseases. Lipids dynamically reside in multiple intracellular locations and their organellar distribution is important for specific interactions and biological function. During brain aging lipid changes have been specifically noted in lysosomes, but the identity of the accumulated lipids, their interactions with other biomolecules such as proteins, and their functional relevance have not been characterized. We used mass spectrometry (MS) to assess longitudinal changes in the lipidome and proteome of lysosomes isolated from the mouse cortex, from the age of 3- to 24-months. Our statistical and machine learning analyses identified two factors demonstrating predictive power for age and differences in both lipids and proteins. Of these, factor 1 was the best predictor of sample age. Factor 1 lipids with the highest feature importance included multiple species of hexosylceramides (HexCer) and their sulfonated derivatives, sulfatides (SHexCer), all of which increased with age. Increased factor 1 proteins included myelin proteins, select sphingolipid catabolism enzymes and proteins associated with lysosomal storage diseases. Our analyses suggested that mechanisms underlying factor 1 encompass the combination of an age-dependent increase in lysosomal delivery of myelin components and alterations in lysosomal sphingolipid catabolism favoring degradation of sphingomyelin over HexCer. The overall age-related lysosomal changes resembled those observed in lysosomal storage diseases, particularly Gaucher disease, where accumulation of HexCer species is associated with lysosomal dysfunction. To corroborate factor 1 predictions, we employed a combination of biochemical, imaging and flow cytometry approaches, which confirmed alterations in sphingolipid catabolism and lysosomal accumulation of myelin components. These changes were associated with age-related alteration in lysosomal morphology, lysosomal dysfunction and inhibition of autophagy in both neurons and microglia. Our findings indicate that factors contributing to lysosomal aging resemble those observed in lysosomal storage diseases and underscore the significance of organelle-specific analyses for dissecting mechanisms contributing to brain aging.

neuroscience↗

bioRxiv2024

Lipid Nanoparticles from L. meyenii Walp Mitigate Sepsis through Multimodal Protein Corona Formation

BackgroundPlant-derived nanoparticles (PDNP) are nano-sized particles isolated from various edible plants that contain bioactive components involved in regulating cellular immune responses against pathogenic intrusion and inflammation. PurposeThis study describes a novel PDNP derived from Lepidium meyenii Walp (maca) that efficiently captures pro-inflammatory cytokines and acute phase proteins in its protein corona to enhance survival in two representative lethal models of sepsis. MethodsLipid nanoparticles were isolated from maca (MDNP) and triacylglycerols and phytoceramides were identified as major constituents using lipidomics. The physicochemical properties of MDNPs were determined, anti-inflammatory effects of MDNP were evaluated using in vitro models and in vivo using endotoxemia and cecal ligation and puncture (CLP) polymicrobial sepsis models. Proteomic analysis of MDNP in healthy or LPS-induced inflammatory plasma was used to determine the composition and inflammatory pathways modulated due to the MDNP protein corona. ResultsIn vitro studies showed that MDNP were non-toxic, reduced macrophage activation, and effectively sequestered pro-inflammatory cytokines to mitigate NF-{kappa}B activity under lipopolysaccharide (LPS) stimulation. In a pre-established LPS-induced endotoxemia model, MDNP-treated mice showed significantly reduced systemic pro-inflammatory cytokines and enhanced survival. Untargeted proteomics and pathway analysis of the MDNP protein corona identified an enrichment in acute phase proteins in MDNP-LPS plasma coronas. MDNP treatment also significantly improved survival in the CLP sepsis model in the absence of antibiotics. ConclusionThis work identified MDNP as an efficient, plant-derived lipid NP that broadly sequesters and neutralizes a compilation of inflammatory mediators in their coronas, offering multimodal therapeutic potential for treating inflammatory diseases.

bioengineering↗