A Pathogenic L2HGDH Variant Impairs Mitochondrial Targeting and Enzyme Function in L-2-Hydroxyglutaric Aciduria: Clinical and Functional Evidence from Two Affected Siblings.

Background: L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive neurometabolic disorder caused by biallelic loss-of-function variants in the L-2-hydroxyglutarate dehydrogenase () gene, leading to accumulation of L-2-hydroxyglutarate in the brain and other tissues. While various variants have been reported, the pathogenic mechanism of specific variants remains unclear. In this study, we aimed to investigate the molecular consequences of the c.

Mitochondria protect against an intracellular pathogen by restricting access to folate.

As major consumers of cellular metabolites, mitochondria are poised to compete with invading microbes for the nutrients that they need to grow. Whether cells exploit mitochondrial metabolism to protect from infection is unclear. In this work, we found that the activating transcription factor 4 (ATF4) activates a mitochondrial defense based on the essential B vitamin folate.

Hexokinase regulates Mondo-mediated longevity via the PPP and organellar dynamics.

The transcriptional complex Mondo/Max-like, MML-1/MXL-2, acts as a convergent transcriptional regulatory output of multiple longevity pathways in . These transcription factors coordinate nutrient sensing with carbohydrate and lipid metabolism across the evolutionary spectrum. While most studies have focused on the downstream outputs, little is known about the upstream inputs that regulate these transcription factors in a live organism.

Building the lab together - from day one.

What are the most challenging and rewarding aspects of starting a new laboratory? In this article, we interview Hans-Georg-Sprenger, who recently started his own research group "Molecular Metabolism & Energy Homeostasis" at the Max Planck Institute for Biology of Ageing in Cologne. From the first PhD student to the first experiments, and from early discoveries and troubleshooting to the first bachelor's thesis defense, the people in the laboratory are central. For Hans-Georg Sprenger, helping others build their skills and independence is what makes mentoring so fulfilling.

2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction.

Mitochondria have a crucial role in regulating cellular homeostasis in response to intrinsic and extrinsic cues by changing cellular metabolism to meet these challenges. However, the molecular underpinnings of this regulation and the complete spectrum of these physiological outcomes remain largely unexplored. In this study, we elucidate the mechanisms driving the whitening phenotype in brown adipose tissue (BAT) deficient in the mitochondrial matrix protease CLPP.

Bacterial Infections Shape Cardiac Macrophages' Response to Ischemia.

Background: Patients with bacterial infections are at increased risk for subsequent cardiovascular events. Whether infections' effects on innate immune cells within the cardiovascular system influence subsequent pathologies remains unclear. Here, we explore cardiac myeloid cells' chronic adaptations to a preceding bacterial insult and implications for subsequent myocardial ischemia.

Single nucleosome imaging reveals principles of transient multiscale chromatin reorganization triggered by histone ADP-ribosylation at DNA lesions.

Timely access to DNA lesions is crucial for genome integrity. This process requires profound remodeling of densely packed chromatin to establish a repair-competent architecture. However, limited resolution has made it impossible to fully understand these remodeling events.

IFN-β production promotes metabolic rewiring and protection against oxidative stress in hepatitis delta virus-infected hepatocyte cultures.

Type I interferons are secreted in response to various stimuli and are used as a treatment for many diseases, including infections with the hepatitis B virus (HBV) and its satellite virus, hepatitis delta (HDV). HDV significantly aggravates HBV-mediated liver damage and is - in contrast to HBV - a strong inducer of interferon responses, including IFN-β. As the role of IFN- β in liver metabolism is so far ill explored, we studied its impact on hepatocyte metabolism in HDV-infected cultures.

Analysis of microRNA expression reveals convergent evolution of the molecular control of diapause in annual killifishes.

Background: Diapause is a condition of developmental arrest in anticipation of adverse environmental conditions present in many diverse taxa. Diapause is a key adaptation that enabled the colonization of ephemeral habitats subject to the alternation of dry and wet seasons by annual killifishes. Upon desiccation of the ponds, killifish embryos remain vital but quiescent in the clay, where they can survive months or even years.

Positron Emission Tomography-Guided Brentuximab Vedotin, Etoposide, Cyclophosphamide, Doxorubicin, Dacarbazine, and Dexamethasone in Older Patients With Advanced-Stage Classic Hodgkin Lymphoma: A Prospective, Multicenter, Single-Arm, Phase II Cohort of the German Hodgkin Study Group HD21 Trial.

Purpose: Positron emission tomography (PET)-guided therapy with 4-6 cycles of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD) is highly effective in younger patients with advanced-stage classic Hodgkin lymphoma (AS-cHL). We report feasibility and efficacy of PET-guided BrECADD as first-line treatment in older patients with AS-cHL.

Patients And Methods: Patients with AS-cHL aged 61-75 years were enrolled in a phase II single-arm cohort of the HD21 trial (ClinicalTrials.

Serine ADPr on histones and PARP1 is a cellular target of ester-linked ubiquitylation.

ADP-ribosylation and ubiquitylation regulate various cellular processes, with the complexity of their interplay becoming increasingly clear, as illustrated by ADP-ribosylation-dependent ubiquitylation mediated by Legionella. Biochemical studies have reported ester-linked ubiquitylation of ADP-ribose by DELTEX ubiquitin ligases, yet the modification sites on cellular targets remain unknown. Here, our search for interactors of RNF114 revealed DNA-damage-induced serine mono-ADP-ribosylation as a cellular target for ester-linked ubiquitylation.

RNA-binding proteins as versatile metabolic regulators.

Metabolic shifts are a hallmark of numerous biological processes, including the differentiation of stem cells along a specific lineage and the activation of diverse cell types, such as immune cells. This review examines the intricate energy metabolic alterations that occur in diverse biological settings, from embryonic development to adult tissue homoeostasis and disease states. In particular, we emphasise the regulatory function of RNA-binding proteins (RBPs) in coordinating these metabolic shifts and examine how they modulate key pathways, such as glycolysis and oxidative phosphorylation, to meet the dynamic cellular energy demands.

Revisiting Genomic Instability, Tumor Microenvironment and Immune Response in High-Grade Serous Ovarian Cancer.

High-grade serous tubo-ovarian cancer is the most common and aggressive type of ovarian cancer characterized by extensive genomic instability and marked inter- and intra-patient tumor heterogeneity. Tumor-site specific signaling crosstalk between cancer cells and the tumor microenvironment influences different tumor ecosystems that drive therapy response and disease progression. Cancer cell-intrinsic genomic aberrations further contribute to the diversity of the tumor immune landscape.

A TFEB-TGFβ axis systemically regulates diapause, stem cell resilience and protects against a senescence-like state.

Diapause is a long-lived state of resilience that allows organisms to outlast adversity. Caenorhabditis elegans can endure months in a fasting-induced adult reproductive diapause (ARD) and, upon refeeding, regenerate and reproduce. Here we find that mutants of ARD master regulator hlh-30/TFEB arrest in a senescence-like state during ARD and refeeding, in which germline stem cells are characterized by DNA damage, nucleolar expansion, cell cycle arrest and mitochondrial dysfunction, alongside dysregulated immune and growth metabolic signatures, elevated senescence-associated β-galactosidase and premature aging at the organismal level.

The role of uremic toxin indoxyl sulfate in the pathophysiology of aortic valve stenosis.

Aims: Chronic kidney disease (CKD) is closely associated with cardiovascular disease (CVD). This includes aortic valve stenosis (AS), one of the most common valve diseases among adults. CKD leads to the retention of uremic toxins such as indoxyl sulfate (IS), which is known to induce inflammatory and pro-calcific processes.

Enhancing autophagy by redox regulation extends lifespan in Drosophila.

Dysregulation of redox homeostasis is implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by HO in vivo, we established a redox-shifted model by manipulating levels of the HO-degrading enzyme catalase in Drosophila. Here we report that ubiquitous over-expression of catalase robustly extends lifespan in females.

The mitochondrial methylation potential gates mitoribosome assembly.

S-adenosylmethionine (SAM) is the principal methyl donor in cells and is essential for mitochondrial gene expression, influencing RNA modifications, translation, and ribosome biogenesis. Using direct long-read RNA sequencing in mouse tissues and embryonic fibroblasts, we show that processing of the mitochondrial ribosomal gene cluster fails in the absence of mitochondrial SAM, leading to an accumulation of unprocessed precursors. Proteomic analysis of ribosome fractions revealed these precursors associated with processing and assembly factors, indicating stalled biogenesis.

CSF1R myeloid-monocytic cells drive CAR-T cell resistance in aggressive B cell lymphoma.

Despite the improvement, approximately 60% of patients with relapsed or refractory (r/r) aggressive B cell lymphoma (B-NHL) do not achieve durable benefit from CAR-T cell therapy. To elucidate factors associated with CAR-T therapy resistance, we conducted high-dimensional analyses of pre- and post-CAR-T cell specimens. In patients with non-durable response, we identified a prognostically relevant lymphoma-associated myeloid-monocytic (LAMM) gene signature.

Phosphoribosyl ubiquitination of SNARE proteins regulates autophagy during Legionella infection.

Legionella pneumophila is an intracellular pathogen that causes Legionnaires' disease. The bacteria release effector proteins, some of which remodel host autophagic-lysosomal pathways. One such effector is RavZ, which delipidates ATG8 proteins, making compromising autophagy in Legionella-infected cells.

Macrophages downregulate NEDD9 to counteract S. Typhimurium- mediated FAK-AKT activation and lysosome inhibition.

The scaffolding protein NEDD9 coordinates signaling downstream of integrins by interacting with focal adhesion kinase (FAK) and thereby promotes cell migration. NEDD9 expression is altered in a number of clinical conditions such as cancer, but its role in innate immunity against infections remains elusive. Transcriptome analysis of Salmonella Typhimurium (ST)-infected murine macrophages showed downregulation of NEDD9 and genes belonging to its signaling network.

SLX4IP acts in parallel to FANCM to limit BLM-dependent replication stress at ALT telomeres.

Alternative Lengthening of Telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that enables cancer cells to gain unlimited replicative capacity. ALT relies on recombination-mediated telomere elongation and is promoted by telomeric replication stress. However, ALT requires strict regulation, as excessive replication stress or recombination are cytotoxic.