Elemental sulfur is an evolutionarily ancient metabolite, yet its generation, storage, and function in animals have remained unclear. We show that mammals harbor elemental sulfur in the form of its most stable allotrope, cyclo-octasulfur (S8). We found that S8 accumulates to millimolar concentrations in mitochondrial membranes and in lipid droplets in both mouse and human cells. We further identified lipid droplet-associated nitric oxide synthase as a source of S8 biosynthesis and found that S8 accumulation in lipid droplets limits lipid peroxidation and suppresses ferroptosis. Accordingly, intra-articular injection of solubilized S8 reduces lipid peroxidation in a mouse model of osteoarthritis. Together, these findings reveal an endogenous pool of S8 in mammals that may protect cells from oxidative membrane damage by modulating cellular sensitivity to ferroptosis.

Heart transplantation following donation after controlled circulatory death (DCD) could alleviate the global shortage of organs. We assessed the cost-effectiveness of this strategy and outlined the factors enabling an efficient DCD heart program. Two strategies were compared: donation after brain death (DBD) using static cold storage vs. DBD + DCD transplantation, where DCD hearts are preserved with a normothermic ex situ perfusion system. Costs (€; 2024 value) and outcomes (quality-adjusted life years (QALYs)) were modelled through a 15-year time horizon. Our main assumption was that DCD would increase transplant access without affecting waitlist mortality, with equivalent post-transplant outcomes. With a 20% annual increase in transplant activity, the DBD + DCD strategy resulted in a mean incremental gain of 0.14 QALYs at an additional cost of €20,618 compared with DBD alone. The incremental cost-effectiveness ratio was €146,373 per QALY gained. An 8% relative reduction in waitlist mortality (i.e., four additional lives saved annually among 500 new waitlisted patients) would make the DCD heart program cost-effective at €100,000 per QALY. Lower consumable costs would further improve cost-effectiveness. Decision-makers should consider these findings in light of the disease severity and the persistent shortage of heart donors that could be alleviated with DCD.

Atherosclerosis (AS) is a chronic lipid-driven inflammatory disease of the arterial wall, and substantial cardiovascular risk persists despite intensive lipid-lowering therapy. Plaque progression depends not only on lipid entry, but also on how vascular wall cells handle intracellular lipids under sustained stress. Lipid droplets (LDs) temporarily sequester excess cholesteryl ester and triacylglycerol, whereas mitochondria use part of the mobilized fatty acid pool and sustain metabolic adaptation. The protective value of LD storage therefore depends on whether it remains linked to effective downstream processing and disposal. Here, lipid droplet-mitochondria (LD-Mito) mismatch describes a loss of coordination between LD turnover and mitochondrial substrate handling. In the plaque environment, this mismatch can shift lipid fate from adaptive buffering toward persistent retention and oxidative injury, thereby reinforcing inflammation and necrotic remodeling. This review examines LD remodeling in macrophages, vascular smooth muscle cells, and endothelial cells; mitochondrial substrate limitation and quality-control imbalance; and the context-dependent regulation of the LD-Mito axis. It further considers how disrupted lipid handling intersects with trained immunity, lipid peroxidation, cell death, and defective efferocytosis. Therapeutically, reducing LD abundance or increasing mitochondrial oxidation in isolation may be insufficient. More effective strategies may require cell- and lesion-specific restoration of coordinated lipid handling while preserving redox control and clearance capacity. The LD-Mito perspective reframes residual plaque risk around a central question: whether intracellular lipids can still reach tolerable downstream fates under sustained atherogenic stress.

Several strategies have been used to mitigate ischemic injury and optimize graft quality in pancreas and islet transplantation, particularly in the context of donation after circulatory death (DCD) donors. These include conventional rapid recovery with static cold storage, optimized DCD retrieval protocols designed to reduce warm ischemia and, more recently, the use of machine perfusion techniques. Normothermic regional perfusion (NRP) represents a distinct approach within this landscape, enabling the restoration of oxygenated blood flow in situ, partial metabolic recovery, and the potential for functional evaluation before organ retrieval. Available clinical experience with NRP in DCD pancreas and islet transplantation indicates that the technique is feasible and safe, with graft and islet isolation results comparable with those achieved with conventional DCD procurement strategies. Nevertheless, overall experience remains limited and important aspects of NRP frameworks require further refinement. This review provides a comprehensive synthesis of the current evidence on DCD beta-cell replacement, with a particular focus on NRP as an emerging strategy to mitigate ischemic injury. We summarize available clinical and registry-based data, discuss the physiological rationale supporting NRP, and outline key gaps in donor selection, perfusion protocols, and outcome assessment. Finally, we identify priorities for future research aimed at optimizing NRP practice and expanding the pancreas donor pool while improving posttransplant graft and patient outcomes.

Mutations in the GBA1 gene, which encodes the lysosomal glucocerebrosidase enzyme GCase, cause the lysosomal storage disorder Gaucher disease and represent the most common genetic risk factor for Parkinson's disease (PD). These mutations deplete lysosomal GCase activity and cause accumulation of GCase substrate, glucosylceramide, and its pathological metabolite, glucosylsphingosine. Impaired GCase activity then drives immune and neuronal dysfunction in Gaucher disease and promotes pathogenic aggregation of α-Synuclein in PD. As such, boosting the lysosomal activity of GCase is a therapeutic strategy to ameliorate substrate accumulation and prevent associated neurotoxicity. To identify the regulators of GCase activity in lysosomes, we conducted a genome-wide screen in primary mouse macrophages using a fluorescent enzyme activity reporter. By validating the screen hits in cellular biochemical and profiling assays, we identified pathways that promote or inhibit lysosomal GCase activity. Our screen identified PLCG2 as a regulator of lysosomal GCase activity. Mechanistically, PLCG2 depletion accumulates Golgi-associated phosphatidylinositols, promoting the transport of mutant GCase into lysosomes while reducing its Golgi-associated pool. Functionally, PLCG2 depletion boosts the activity of lysosomal mutant GCase, the cellular flux of glucosylceramide, and the clearance of pathogenic GCase substrates. In summary, our screen has uncovered the regulators of GCase abundance and trafficking at a whole-genome scale and identified potential pathways for future therapeutic interventions in Gaucher and Parkinson's to boost the activity of this enzyme in lysosomes.

The Faroe Islands are home to descendants of a North Atlantic founder population with a unique history shaped by both migration and periods of relative isolation. Here, we investigate the genetic diversity, population structure, and demographic history of the islands by analyzing whole genome sequencing data from 40 participants in the Faroe Genome Project. This represents the first whole genome sequencing panel of this size from the Faroe Islands. We observed numerous putatively functional private alleles, including stop gain variants and high impact missense variants in the cohort. Faroese individuals had a higher proportion of their genomes contained in long runs of homozygosity than other European groups, including Finnish, suggesting a more recent or stronger bottleneck in the Faroese population. Signals of positive selection were identified at loci containing genes that play roles in vitamin D and dietary fat absorption and DNA repair, while increased diversity on lactase persistence haplotypes was observed. Fine-scale analysis of haplotype structure in present-day and ancient European genomes revealed genetic affinities with ancient Iron Age individuals from the North and West of Europe, providing evidence for potential contributions to the Faroese gene pool from Celtic and Viking populations as well as information about the temporal order in which these events happened. This study highlights the impact of evolutionary processes, such as ancient admixture, founder events, and positive selection, on the present-day genetic architecture of North Atlantic founder populations like the Faroe Islands.

Intracellular lipid storage is mediated by lipid droplets. Once considered inert lipid inclusions, these structures are now recognized as ubiquitous, multifunctional organelles at the core of cell biological control of metabolism. Lipid droplet dysfunctions are linked to a range of metabolic diseases including obesity, diabetes, steatohepatitis, and lipodystrophy. Intriguingly, not all lipid droplets are the same. Striking structural and functional differences are regularly observed between the lipid droplets of different tissues and cell types, and even within the lipid droplet pool of a single cell. Here, we discuss the current views on the molecular mechanisms that create and maintain this high degree of lipid droplet heterogeneity.

The study of natural spontaneous fertile hybrids, whose parent species is Ae. trivialis Migusch. et Chak (2n = 42), is of great importance for expanding the genetic pool of the genus Triticum L., which is a crucial part of current and future breeding efforts. The number of wild relatives-potential sources of valuable disease resistance genes-is quite large for common wheat: these include species of the genera Tritium, Aegilops, Agropiron, Secale, Haynaldia, Villosa, and others. In addition to disease and pest resistance, wild species offer frost resistance, drought tolerance, salt tolerance, and increased protein quantity and quality. The primary objective of this study was to identify new, genetically diverse source material for common wheat breeding based on botanical and morphological studies, as well as to register new spontaneous Aegilops-wheat hybrids using electrophoretic analysis of storage proteins. To achieve the research objective, the following tasks were set and solved: Aegilops-wheat hybrids were studied and recorded using protein formulas; spontaneous fertile Aegilops-wheat hybrids were analyzed using laser microscopy and tandem mass spectrometry. In this study, we demonstrated differences between the studied spontaneous hybrids using metabolomic analysis and laser microscopy, as well as identified differences in the protein spectra of the spontaneous hybrids and their maternal form, K-1386. These spontaneous Aegilops-wheat hybrids will be used in further work to identify their paternal form. It should be noted that it is advisable to use the studied spontaneous Aegilops-wheat hybrids in future breeding to expand the gene pool of the genus Triticum L. and to obtain new heterogeneous forms.

Alzheimer's disease (AD) is a widespread age-related neurodegenerative disorder. Current therapies targeting Aβ plaques and hyperphosphorylated Tau show limited efficacy. The core pathology of AD involves neuroglial metabolic network collapse, which is tightly associated with brain iron dyshomeostasis and abnormal ferroptosis. As the main iron storage and antioxidant cells in the CNS, astrocytes transform into disease-associated astrocytes under AD conditions. Metabolic reprogramming switches them from a neuroprotective to a pro-ferroptotic phenotype, contributing to thereby exacerbating systemic metabolic dyshomeostasis. This review systematically elaborates the regulatory mechanisms of astrocytic ferroptosis in AD: disordered iron metabolism (e.g., aberrant DMT1/FPN1 expression) induces iron accumulation as the initiation prerequisite; excessive oxidative stress (Ang II/HIF-1α-NOX4 axis-mediated ROS generation) and impaired antioxidant defense (Nrf2-SLC7A11/GPX4 inactivation, ApoE4 dysfunction) serve as core regulatory modules; FTH1 and SAT1 dysregulation elevates the labile iron pool, while AQP4 dysfunction impairs metabolite clearance, amplifying ferroptosis. Moreover, aberrant crosstalk among astrocytes, microglia and oligodendrocytes exacerbates AD-related neurodegeneration. Collectively, astrocytic ferroptosis acts as a key integrative mechanism linking iron dysmetabolism, oxidative stress, neuroinflammation and Aβ/Tau pathology, offering a potential new avenue for decoding AD pathogenesis. Targeting astrocytic ferroptosis is expected to overcome the long-standing therapeutic limitations of conventional AD treatments, providing theoretical support and new directions for developing disease-modifying AD therapies. While individual components including disease-associated astrocytes, brain iron dyshomeostasis, NOX4- and NRF2-related ferroptosis have been documented separately, this review represents the first comprehensive synthesis that identifies astrocytic ferroptosis as a central hub that unifies these fragmented mechanisms into a cohesive pathogenic cascade driving AD.

Enteric coccidian parasites harm agriculture and human health. Infectious, sporulated parasites eventually senesce. Here, we examined transcriptional changes in sporulated oocysts of Eimeria acervulina stored for 4-30 months at 4 °C. Precipitous decline in RNA abundance and transcription followed an interval of stability. Sixty constitutively expressed genes each contributed > 1000 transcripts per million (TPM) throughout, including a serine protease inhibitor, surface antigen genes, a cation-transporting ATPase, an oocyst wall protein, a zinc finger DHHC domain-containing protein, and highly expressed hypothetical proteins with no known function. Strikingly, ~82% of 6867 annotated genes underwent differential expression when comparing freshly sporulated parasites to those held for 30 months; nearly one-third of these underwent significant expression change. In freshly sporulated oocysts, 86 significantly DEGs exceeded 1000 TPM; these encoded heat shock proteins, lactate dehydrogenase, glucose-6 isomerase, and various hypothetical proteins. The oldest parasites expressed 66 DEGs, including many ribosomal subunits, a haloacid dehalogenase-like hydrolase domain-containing protein, and various hypothetical proteins. Taken together, these findings helped us to identify markers of mature parasites that remain relatively abundant in the transcript pool as oocysts age and identify other transcripts (e.g., ribosomal RNA) that increase in their relative abundance even as RNA abundance declines in senescent parasites.

The fertilized egg relies almost entirely on maternal stores in the oocyte to ensure the successful initiation of development[1]. The cytoplasmic lattices (CPLs) in mammalian oocytes store maternal-expressed proteins and have an essential role in embryogenesis[2,3]. Impairing multiple CPL members leads to early embryonic arrest, resulting in infertility in mammals. However, the mechanism underlying the assembly and storage of CPLs remains largely unknown. Here we report the cryo-electron microscopy structure of a native mouse CPL repeating unit (approximately 4 MDa) at 3.74 Å resolution. This repeating unit exhibits a tripartite architecture comprising a framework, extended linkers and a CPL core. The external framework is built from PADI6 decamers and the subcortical maternal complexes. Two linkers formed by NLRP4F polymerize the frameworks into an extended filament. In the CPL core, the epigenetic regulator UHRF1 is trapped by PADI6, UBE2D and NLRP14 in a compact, autoinhibited conformation that prevents nuclear entry and ubiquitin ligase activity. Moreover, the CPL core stores GTP-bound α/β-tubulin heterodimers and inactive SCF E3-ubiquitin ligase components (FBXW-SKP1 complex) in a poised but restrained state. These features establish CPLs as a dynamic regulatory pool that enables rapid microtubule assembly and tightly controlled ubiquitination during the oocyte-to-embryo transition. Together, this semi-in situ structure illuminates CPL assembly and storage-module organization, and establishes CPLs as specialized proteostasis organelles for maternal regulation in oocytes and early embryonic development.

Mitochondrial ferritin (FtMt), first identified by Levi et al., is an iron-storage protein with high homology with cytoplasmic ferritin. It is mainly expressed in metabolically active tissues and exhibits distinct physiological and biochemical properties compared cytoplasmic ferritin. Over the past few decades, significant attention has been drawn to the unique structural and functional characteristics of FtMt that differentiates it from conventional ferritin. Mitochondrial ferritin specifically located on the mitochondrial exhibits unique advantages in mitochondrial redox balance through isolating iron within mitochondria, reducing oxidative stress and maintaining mitochondrial homeostasis. Moreover, it modulates the labile iron pool within mitochondria, facilitating the biosynthesis of iron-sulfur clusters and supporting cellular respiration. This review comprehensively discusses the pivotal function of FtMt in regulating mitochondrial redox homeostasis and its impact on cell fate decisions, specifically, its influence on apoptosis, ferroptosis through alterations in mitochondrial integrity. We also summarize recent advances in understanding the association between FtMt dysregulation and various diseases, emphasizing its implications in neurodegenerative diseases, cardiovascular disorders and cerebrovascular pathologies. By critically evaluating emerging evidence, this article aims to provide translational insights into targeting FtMt and mitochondrial redox homeostasis as therapeutic strategies for mitigating these clinically significant diseases.