Neuroinflammation is increasingly recognized as a critical contributor to epileptogenesis and pharmacoresistance in temporal lobe epilepsy (TLE). MicroRNAs (miRNAs) are key post-transcriptional regulators of immune signaling, neuronal excitability, and inflammatory responses; however, their contribution to treatment resistance remains incompletely understood. This study aimed to characterize peripheral neuroinflammatory miRNA signatures associated with pharmacoresistance in TLE and evaluate their discriminatory performance and correlation-based co-expression patterns. In this cross-sectional study, 80 patients with TLE were stratified into responders (n = 40) and non-responders (n = 40) according to International League Against Epilepsy criteria for treatment response. Expression levels of ten candidate miRNAs implicated in neuroinflammation, neuronal homeostasis, and apoptosis were quantified in peripheral blood mononuclear cells (PBMC) using RT-qPCR. Differential expression, receiver operating characteristic (ROC), and correlation-based network analyses were performed. Responders exhibited significantly higher expression of miR-146a, miR-132, miR-139, miR-128, and miR-29b, whereas non-responders demonstrated increased expression of miR-21, miR-155, miR-223, and miR-34a. Among individual miRNAs, miR-128 (AUC = 0.77) and miR-146a (AUC = 0.75) showed the strongest discriminatory performance. Pharmacoresistant TLE is associated with a distinct pattern of neuroinflammatory miRNA dysregulation and altered correlation network organization. Collectively, these findings support the concept that peripheral neuroimmune alterations are associated with pharmacoresistance and identify PBMC-derived neuroinflammatory miRNAs as promising candidate biomarker signatures supporting further validation in larger, independent cohorts with prospective study design.
Mitochondria integrate metabolic, signalling, and quality-control pathways that are critical for neuronal and glial homeostasis. Beyond ATP production, they regulate redox balance, calcium dynamics, proteostasis, innate immune signalling, and the molecular pathways governing cell survival and death. This Closing Editorial synthesizes the main advances reported in this Collection across neurodegeneration, neurodevelopmental vulnerability, inherited mitochondrial disorders, neurotrauma, drug-induced neurotoxicity, and neuroimmune regulation. Collectively, these studies establish mitochondrial dysfunction as a heterogeneous and context-dependent process rather than a uniform or secondary consequence of neurological disease. Mitochondrial alterations are dynamically regulated across cell types, subcellular compartments, and disease stages, and are tightly coupled to inter-organelle communication and cellular stress-response pathways. The contributions highlight convergent mechanisms linking astrocytic mitochondrial DNA damage, dysregulated RNA-binding proteins, altered mitochondria–endoplasmic reticulum contacts, disrupted iron and redox homeostasis, and mitochondrial–inflammatory signalling to neuronal vulnerability and impaired circuit integrity. They also identify potential therapeutic targets while defining key unresolved questions, particularly the need to establish mechanistic causality, delineate cell- and compartment-specific mitochondrial responses, and validate findings using clinically relevant models and outcome measures. Overall, this Collection positions mitochondrial biology as a mechanistic framework connecting metabolic dysfunction, cellular stress, neuroinflammation, and neuronal degeneration, and supports its development as a therapeutic target for disease-modifying interventions in neurological disorders.
Diabetes Mellitus (DM) is a major comorbidity that exacerbates ischemic brain injury and hinders functional recovery following stroke. Given that angiogenesis and the maintenance of blood-brain barrier (BBB) integrity are essential for neurorestoration, understanding how DM influences these processes and the molecular mechanisms involved is critical for improving clinical outcomes. To investigate these effects, a type 1 DM model was established in six-week-old mice via intraperitoneal injections of streptozotocin (60 mg/kg/day for 5 days), with success confirmed by blood glucose testing two weeks later. Focal ischemic stroke was subsequently induced using a photothrombosis model. Functional recovery was assessed using neurological scoring, the Rotarod test, and the foot-fault test. Post-stroke neovascularization was quantified via lectin injection, while BBB integrity was evaluated through IgG leakage, pericyte coverage, and the expression of tight junction proteins (Zo-1, occludin, and claudin-5). Additionally, protein expression within the Slit2/Robo/CRTC1 pathway was analyzed 1, 7, and 14 days post-stroke using immunofluorescence and western blotting. Our results demonstrated that DM significantly impaired sensorimotor recovery and hindered reparative neovascularization in the peri-infarct area. Furthermore, DM exacerbated BBB disruption, as evidenced by increased IgG leakage, reduced expression of occludin and claudin-5, and diminished pericyte coverage. Mechanistically, DM led to a decrease in Robo1 and an increase in Robo4 expression without altering Slit2 levels. Additionally, DM further suppressed the expression of the co-transcription factor CRTC1 following the ischemic event. Our findings indicate that DM impairs post-stroke angiogenesis and BBB repair accompanied by the dysregulation of the Slit2/Robo/CRTC1 signalling pathway. These results highlight a potential therapeutic target for enhancing stroke recovery in diabetic populations.
Drug-resistant epilepsy involves persistent remodeling of the epileptogenic tissue microenvironment. In temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), it remains unclear whether microglia exhibit uniform inflammatory activation or structured state-level reconfiguration. We integrated single-cell RNA sequencing data from GSE190452 with an independent bulk RNA sequencing cohort, GSE256068. Microglial state signatures derived from the single-cell dataset were projected into bulk tissue, and abundance-adjusted models and a non-overlap sensitivity analysis were used to distinguish state-associated remodeling from changes in microglial representation. Associations of ST6GAL1 and CX3CR1 with microglial state programs were explored. HMC3 human microglia-like cells were used for exploratory CX3CL1–CX3CR1 pathway-level assays under magnesium-free conditioned-medium stimulation. Single-cell analysis identified 5,963 microglia/myeloid cells and nine transcriptional state programs, with marked inter-individual heterogeneity and no consistent global inflammatory shift. In the bulk validation cohort, a C1Q/antigen-presentation-like program was the most reproducibly elevated microglial signature in TLE-HS and remained associated with disease status after adjustment for microglial abundance. Inflammatory-output signals were attenuated after abundance adjustment, whereas amplification-prone signatures showed limited reproducibility. ST6GAL1 and CX3CR1 preferentially tracked the C1Q/antigen-presentation-like program. In HMC3 cells, CX3CL1 treatment was accompanied by lower inflammatory mediator release and reduced nuclear factor-κB p65 nuclear localization, while CX3CR1 antagonism partially reversed these patterns. Human epileptogenic tissue exhibits structured microglial state reconfiguration rather than uniform immune activation. The C1Q/antigen-presentation-like program represents a reproducible lesion-associated signature, while ST6GAL1/CX3CR1 findings remain exploratory candidate associations.
The conceptual evolution of Parkinson’s disease (PD) from a protein-centric disorder to a metabolic disease has gained substantial momentum. While the lipidopathy framework encompasses dysregulation across all lipid classes, the emerging fatty acidopathy concept offers a mechanistically tractable refinement, focusing on fatty acid side-chain dyshomeostasis as a critical determinant of α-synuclein conformation and aggregation. This short review argues that fatty acidopathy is a mechanistically defined, conditionally applicable subset within the broader lipidopathy framework, with relevance that varies across PD subtypes. We examine the hierarchical relationship between these concepts, the evidence supporting fatty acidopathy in α-synuclein-driven PD, and the therapeutic implications of targeting upstream metabolic dysregulation. We critically discuss the translational challenges of current lipidomic approaches, including distinguishing disease-specific from state-specific metabolic signals, defining pathological trigger points, and validating biomarkers across diverse populations. We acknowledge that current evidence remains largely associative and that rigorous, stratified trial designs are required to bridge the preclinical-to-clinical gap. The fatty acidopathy framework offers a conceptual foundation for future subtype-specific therapeutic development in PD.
Parkinson’s disease (PD), the second most common neurodegenerative disorder, is characterized by dopaminergic neuron loss and glial dysregulation. Oligodendrocytes (OLs) support neuronal function through myelination, metabolic coupling, and trophic functions. However, their roles and regional vulnerability patterns in PD remain unclear. We reanalyzed a public single-nucleus RNA-seq dataset from the substantia nigra pars compacta of 29 individuals (15 with PD and 14 controls), together with an independent multi-region dataset comprising 100 individuals (75 with PD and 25 controls). After quality control, we performed clustering, differential expression, pathway enrichment, and cell–cell communication analyses, focusing on OL-specific transcriptomic alterations, subpopulation heterogeneity, and cell death–related programs. Cross-dataset validation and cell-type–resolved analyses were further performed to assess robustness and resolve regional heterogeneity. OLs had the highest scDist point estimate among the evaluated cell types. Upregulated OL genes showed proteostasis- and stress-related pathway enrichment, whereas downregulated genes were enriched in synaptic- and neuroactive ligand–receptor signaling pathways. An ALDH1A1-high OL subcluster showed metabolic reprogramming and ferroptosis activation. Cell-cell communication analysis revealed impaired neuron-OL interactions, with attenuation of neuronal NRG1-ERBB4 signaling. In the independent dataset, OLs consistently exhibited prominent transcriptional perturbations across brain regions. Across regions, OLs showed region-dependent enrichment of apoptosis- and necroptosis-related pathways, whereas MAPK signaling was consistently enriched. Cross-dataset analyses identify OLs as a prominently altered and regionally heterogeneous cell population in PD, with transcriptional patterns consistent with metabolic vulnerability, ferroptosis-related stress, altered MAPK signaling, and attenuated NRG1–ERBB4 neuron–OL communication.
Ischemic stroke triggers a rapid immune infiltration to the brain, reshaping its cell type composition and possibly confounding the analysis of immune cell enriched molecules. MicroRNAs (miRNAs) act as powerful regulators by fine-tuning messenger RNA (mRNA) expression, thereby modulating cell type specific responses to ischemia. Several bulk tissue analyses suggest elevated levels of anti-inflammatory miRNA, miR-223-3p, in ischemic stroke but pathological relevance of this deregulation remains unclear due to lack of single-cell resolution. We show that miR-223-3p is acutely increased in ischemic stroke patients’ blood and selectively expressed in myeloid cells in mice. Due to myeloid specificity of miR-223-3p, it appears massively elevated in bulk ischemic brain lysates, although the elevation primarily reflects increased myeloid cell abundance rather than per-cell upregulation in the brain. Strikingly, brain infiltrating macrophages exhibited acutely reduced miR-223-3p levels. We hypothesize that these macrophages initially acquire a more proinflammatory phenotype than the brain resident macrophages, and re-analysis of single-cell transcriptomics (GSE234052) further supported a proinflammatory macrophage phenotype after acute cerebral ischemia. Our study exemplifies the inherent limitations of bulk tissue analyses and underscores the need to revisit conclusions drawn from the tissue-level data, especially when immune cell infiltration and enrichment of a molecule is suspected. Overcoming the technical challenges of integrated spatial miRNA and mRNA detection at single-cell resolution will be essential to dissect the regulatory mechanisms underlying ischemic stroke pathology and to inform the development of effective immunomodulatory therapies. Increased brain miR-223-3p in ischemic stroke is caused by changes in cell type composition. In healthy brain, miR-223-3p is expressed by microglia and resident macrophages. Ischemia causes infiltration of miR-223-3p-rich peripheral myeloid cells to the brain, increasing the level of miR-223-3p in tissue lysates. In ischemic macrophages, miR-223-3p was decreased while no deregulation was found in microglia.
Traumatic brain injury (TBI) is a major cause of disability and mortality among children and adolescents. A central concern in pediatric TBI is not only focal tissue cavitation but also progressive global and regional brain-volume loss, cortical thinning, white matter disruption, and the resulting impairment of neurodevelopmental function. In this review, “immature brain” is used as an umbrella term spanning neonatal, early postnatal or infant, juvenile or childhood, and adolescent stages; these stages are not treated as biologically equivalent. We analyze developmental vulnerability after TBI, compare focal lesion, tissue-loss, and brain-atrophy trajectories while distinguishing direct within-study age comparisons from cross-study interpretations, summarize experimental models with particular attention to focal and diffuse or white matter injury paradigms, and discuss MRI metrics, biomarkers, and candidate therapeutic strategies relevant to pediatric outcomes.
Microglia are highly dynamic tissue-resident macrophages that continuously adapt their functional states to developmental, environmental, and pathological cues within the central nervous system (CNS). Rather than executing fixed genetic programs, microglial phenotypes emerge from continuous integration of developmental origin, regional niche, metabolic status, neuronal activity, and environmental signals. In early brain development, microglia contribute to neural circuit refinement through phagocytosing apoptotic cells and extraneous synapses in an activity-dependent manner. In contrast, in the mature CNS, they continuously monitor their surroundings, maintaining synaptic homeostasis and rapidly responding to local tissue perturbances. However, perturbations in the spatiotemporal coordination of state transitions, such as ageing, metabolic dysregulation, and chronic disease, can redirect microglia toward maladaptive phenotypes characterized by long-term inflammation, impaired phagocytosis, and neuronal damage. Building upon recent advances in single-cell transcriptomics, spatial biology, and systems neuroscience, this review synthesizes current understanding of how developmental programming, regional specialization, temporal regulation, and metabolic adaptation collectively shape dynamic microglial states across health and disease. Finally, we discuss emerging therapeutic strategies aimed at context-dependent modulation of microglial states while highlighting current challenges and unanswered questions for precision microglial therapies. Microglia are highly plastic CNS-resident immune cells whose functional states are continuously shaped by developmental history, spatial niche-derived signals, temporal regulation, metabolic remodeling, and local microenvironmental cues. Rather than progressing through fixed activation programs, microglia dynamically transition among homeostatic, adaptive, and maladaptive states according to physiological demands and disease context. Failure to appropriately regulate these state transitions promotes chronic neuroinflammation, impaired phagocytosis, metabolic dysfunction, and neurodegeneration. Consequently, emerging therapeutic strategies increasingly focus on restoring physiologically coordinated microglial state dynamics through spatiotemporally informed modulation of signaling pathways, immunometabolism, epigenetic programs, and tissue-specific regulatory networks. (This figure was initially generated with the assistance of an AI tool (ChatGPT) and subsequently substantially modified by the authors to ensure scientific accuracy and originality.)
Lactate has traditionally been viewed as a metabolic substrate that supports neuronal energy demands through the astrocyte–neuron lactate shuttle. Increasing evidence indicates that lactate also functions as a context-dependent signaling metabolite and as a precursor for lysine lactylation. In this review, we use the term “lactate code” as a working framework, not as an established molecular code, to organize how lactate-related signals may acquire different meanings in Alzheimer’s disease (AD). This framework emphasizes five variables: lactate source, responding cell type, modified substrate, subcellular compartment, and disease stage. Under physiological conditions, astrocyte-derived lactate supports synaptic plasticity and memory through monocarboxylate transporter-dependent trafficking. In AD models, this supportive axis may be impaired, producing a functional deficit in neuron-usable lactate. In parallel, amyloid-β plaques can promote glycolytic reprogramming of peri-plaque microglia, leading to local lactate-associated inflammatory niches and histone lactylation events such as H4K12la–PKM2 and H3K18la–NF-κB-related signaling. In neurons, lactylation appears highly substrate-specific. APP-K612 lactylation has been reported to reduce APP–BACE1 interaction, enhance APP–CD2AP-mediated endosomal–lysosomal routing, and suppress amyloid-β production, whereas tau lactylation at K331 and K677 has been associated with impaired ubiquitination, increased phosphorylation or cleavage, ferritinophagy, ferroptosis, and proteostasis failure. These findings remain emerging and require independent validation in additional models and human cohorts. The framework helps explain why bulk lactate measurements, especially in cerebrospinal fluid, show inconsistent associations with AD. Future work should move beyond total lactate levels toward spatial lactylomics, site-specific causal models, isomer-resolved lactylation assays, and clinically measurable biomarkers. More broadly, lactate signaling should be considered alongside other metabolic abnormalities in neurodegeneration, including mitochondrial dysfunction, oxidative stress, altered nitrogen metabolism, and neuroinflammation.
Myocardial infarctions (MI) can lead to post-MI cardiac and neurocognitive dysfunctions due to the complex interplay of the neurocardiac “brain and heart” axis. Imbalanced autonomic nervous system (ANS) synchronization within the neurocardiac axis leads to infarcted or damaged tissues. This may influence potential inflammatory signaling mechanisms in post-MI pathology and, by extension, the repercussions of acute and chronic MI outcomes. Here, previous in-vivo experimental rodent and porcine models with surgically induced MI/heart failure (HF) and in-vitro models report brain-heart association regions and pathologies. Furthermore, clinical meta-analyses were compiled to provide a broad overview of the varying impacts of post-MI pathologies on the brain and heart. Other supplemental perspectives postulate other relevant inflammatory mechanisms, such as neurohumoral imbalances, a weakened immune system, and genetic predispositions, which expand a more holistic view of post-MI mechanisms. By examining in closer detail the inflammatory cells (e.g., microglia and astrocytes) and the blood-brain barrier (BBB), cardiogenic trauma from MI incites chronic systemic inflammation and exacerbates the stress response. This further weakens the BBB, prolongs neuroinflammation, and damages sites responsible for cardiac regulation and repair. Myocardial infarctions and their complications impact millions worldwide. Thus, it is imperative to understand the inflammatory pathways disrupted by the neurocardiac axis and their functional outcomes.
Adult hippocampal neurogenesis in the dentate gyrus (DG) is essential for maintaining normal hippocampal function. Although activation of transient receptor potential vanilloid 4 (TRPV4) has been reported to regulate neural stem cell proliferation and dendritic development, its long-term effects on the survival of newborn neurons and hippocampal function remain unclear. Here, chronic activation of TRPV4 with the agonist GSK1016790A markedly reduced the numbers of 28-day-old BrdU⁺ and BrdU⁺/NeuN⁺ cells in the DG of adult male ICR mice (GSK mice), accompanied by decreased NeuN protein levels, indicating impaired survival of mature newborn neurons. In addition, 28-day-old BrdU⁺/NeuN⁺ neurons exhibited an altered spatial distribution in GSK mice, with an increased proportion retained within the subgranular zone and a corresponding reduction in the outer granule cell layer. Chronic TRPV4 activation also impaired long-term potentiation, reduced dendritic spine density, and decreased the expression of NR1, NR2A, NR2B, postsynaptic density protein 95 (PSD95), and synaptophysin. These alterations were accompanied by reduced activation of the Ras-Raf1-MEK-ERK1/2-CREB, PI3K-Akt-GSK3β-CREB, and PI3K-Akt-mTOR signaling pathways. Notably, pharmacological activation of PI3K or ERK restored the survival and altered spatial distribution of newborn neurons, dendritic spine density, synaptic protein expression, synaptic plasticity, and spatial learning and memory performance in GSK mice. Collectively, these findings demonstrate that chronic TRPV4 activation disrupts adult hippocampal neurogenesis, synaptic function, and cognition. These pathological changes were associated with reduced activation of ERK- and PI3K-related signaling pathways, suggesting that the downregulation of these pathways may contribute to the detrimental effects of chronic TRPV4 activation on hippocampal function. TRPV4 Activation Impairs Neurogenesis, Synaptic Function, and Cognition Activation of TRPV4 impairs adult hippocampal neurogenesis, synaptic structure and function, ultimately contributing to cognitive impairment. These alterations are associated with the downregulation of the PI3K-Akt and Ras-Raf1-MEK-ERK1/2 signaling pathways
Neuroinflammation is a central driver of numerous neurological disorders. While granzymes have classically been studied as cytotoxic effector molecules secreted from immune cells along with the pore-forming molecule, perforin, accumulating evidence suggests that these serine proteases also play roles in non-cytotoxic, neuroinflammatory processes. This review summarizes the current and emerging paradigms related to how granzymes contribute to the progression of neuroinflammation and neurological diseases. Taken together, current research supports a pathogenic role for granzymes as key mediators linking immune activation to neuronal damage and sustained neuroinflammation. Investigating granzyme-modulated neuroinflammatory responses in the CNS may unveil new avenues for therapeutic intervention in neuroinflammatory and neurodegenerative disorders.
Zika virus (ZIKV) infection during early development is associated with severe neurodevelopmental impairment, including congenital microcephaly, yet the molecular mechanisms linking viral exposure to neuronal dysfunction remain incompletely understood. Ndel1 (nudE neurodevelopment protein 1 like 1) is an oligopeptidase critically involved in neuronal migration, neurite outgrowth, and cytoskeletal dynamics, processes essential for proper brain development. Building on previous observations that Ndel1 enzymatic activity is reduced in ZIKV-infected embryonic and neonatal brains, we investigated whether this modulation represents a conserved host response or a strain-specific molecular effect. Using a neonatal intracerebroventricular infection model in Swiss mice at postnatal day 0, we compared the effects of a Brazilian ZIKV strain (ZIKVBR), an African lineage strain (ZIKVAF), and dengue virus (DENV) on Ndel1 regulation in the brain. We found that Ndel1 enzymatic activity was significantly reduced at early post-infection time points (P3 and P7) exclusively in ZIKVBR-infected animals, whereas ZIKVAF and DENV did not alter enzyme activity relative to controls. Notably, at the earliest timepoint (P3), this reduction occurred in the absence of changes in Ndel1 mRNA expression, indicating an initial post-transcriptional or functional mechanism of regulation, although Ndel1 mRNA expression was also significantly reduced by P7. Although both ZIKV strains induced robust inflammatory gene expression, only ZIKVBR infection resulted in decreased Ndel1 activity, dissociating neuroinflammatory signaling from enzymatic modulation. Importantly, this strain-specific reduction parallels the unique capacity of ZIKVBR to induce microcephaly and supports Ndel1 dysfunction as an early molecular event associated with neurodevelopmental impairment. Together, these findings identify a virus- and strain-specific regulation of a key neuronal enzyme and provide mechanistic insight into the molecular basis of ZIKVBR-associated neurodevelopmental outcomes.
Death-associated Protein Kinase-1 is a Ca2+/calmodulin- dependent serine/threonine protein kinase which controls various cellular processes and functions, including apoptosis, autophagy, and post-transcriptional processes, through multiple microRNAs. Increasing evidence suggests that, aberrant increase in the level of DAPK1 may result in neuronal injury and neurodegeneration by integration of multiple pathological processes such as excitotoxicity, neuroinflammation, and protein aggregation. DAPK1 contributes to disease progression through mechanisms such as NMDA receptor-mediated excitotoxicity, tau and α-synuclein hyperphosphorylation, apoptotic signaling, autophagic dysregulation, and synaptic loss. This review overviews the structural organization, regulatory mechanisms and role of DAPK1 in various cellular processes involved in neurodegeneration. This review discusses the complex transcriptional, post-transcriptional, and post-translational mechanisms governing DAPK1 activity, including regulation by transcription factors, microRNAs, phosphorylation events, and protein degradation pathways. Particular highlighting is given to the involvement of DAPK1 in both chronic and acute neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, diabetic encephalopathy, traumatic brain injury, and cerebral ischemic stroke. Finally, current therapeutic approaches based on the modulation of DAPK1 activity, including kinase inhibitors, competitive peptides, and gene-regulatory approaches, are reviewed, along with the challenges associated with target selectivity, blood–brain barrier penetration, and clinical translation. Collectively, this review emphasizes the therapeutic potential and discusses future directions for the development of disease-modifying interventions targeting DAPK1 in neurodegenerative diseases.
Mitochondrial dysfunction is a central pathogenic mechanism in Parkinson’s disease (PD), yet early mitochondrial events linking respiratory impairment to neuronal vulnerability remain incompletely defined. Here, we investigated the impact of acute and chronic exposure to subtoxic and toxic doses of the mitochondrial Complex I inhibitor rotenone on oxidative stress, mitochondrial bioenergetics/metabolism, and mitochondrial dynamics in primary cortical neurons. Using live-cell imaging, bioenergetics and metabolomic profiling, we show that nanomolar concentrations of rotenone rapidly induce accumulation of reactive oxygen species (ROS), lipid peroxidation, and loss of mitochondrial membrane potential preceding overt neuronal death. Notably, high-content morphometric analysis revealed that even subtoxic doses of rotenone trigger an early structural remodeling characterized by mitochondrial network fragmentation into small spherical puncta (0.5–3 μm) and localized organelle swelling at both neuritic and synaptic levels. Instead, at the molecular level, whole-cell biochemical degradation of mitochondrial remodeling proteins, suppression of regulated, physiological fission–fusion cycling and accumulation of the autophagy adaptor SQSTM1/p62, indicative of defective quality control, fully manifest only at higher, toxic rotenone concentrations. Furthermore, subtoxic doses elicit widespread metabolic alterations including persistent redox imbalance, impaired glutathione (GSH) biosynthesis, and downregulation of anabolic processes such as folate/one-carbon and amino sugar metabolism. Collectively, our findings newly reveal that localized mitochondrial morphometric remodeling and metabolic pathway rewiring represent early, interconnected adaptive responses to complex I impairment, contributing to the baseline thresholds of neuronal vulnerability in PD models.
Mitochondria have long been organelles, recognized as bioenergetic organelles. Additionally, mitochondria have recently emerged as central hubs of RNA regulatory networks. A growing body of evidence demonstrates that mitochondria and RNA-binding proteins (RBPs) engage in a two-way dialogue to integrate stress responses, proteostasis, and adaptive cellular programs. Several RBPs linked to neurodegenerative diseases, such as TDP-43, FUS, TIA-1, TIAR, and Pumilio family proteins, directly impact mitochondrial biogenesis, fusion–fission dynamics, and mitophagy. In turn, mitochondrial signaling can reprogram RBP behavior via post-translational modification, recruitment to mitochondrial membranes, and stress-induced translocation to cytoplasmic ribonucleoprotein granules. Interference with this regulatory axis significantly impacts on neuronal homeostasis. Mislocalization of RBPs is often linked to mitochondrial fragmentation, compromised oxidative phosphorylation, decreased ATP production, and increased reactive oxygen species (ROS) production. Notably, mitochondrial dysfunction is a common early event, even before apparent neuron loss, in several neurodegenerative diseases. Emerging data also points to a role for the mitochondria RBP interface in selective neuronal vulnerability, particularly in motor neurons that rely heavily on both mitochondrial bioenergetics and highly regulated RNA metabolism. Here, we review recent work that has helped define the molecular underpinnings of mitochondrial RBP crosstalk, discussing emerging tools that have facilitated these findings (including super-resolution microscopy, RNA interactome mapping, and mitochondrial proteomics), while highlighting therapeutic approaches that seek to restore mitochondrial and RNA homeostasis. Understanding the interface between mitochondria and RBPs provides a novel paradigm for neurodegeneration and may open new therapeutic opportunities. Mitochondria and RNA-binding proteins (RBPs) establish a bidirectional regulatory axis that links cellular metabolism with stress-responsive RNA processing and proteostasis. The interruption of this crosstalk triggers a self-perpetuating pathogenic cycle marked by mitochondrial fragmentation, compromised oxidative phosphorylation, and increased reactive oxygen species, which subsequently leads to the mislocalization and aggregation of RBPs. These defects result in extensive RNA dysregulation and proteostatic failure, ultimately undermining neuronal homeostasis and facilitating neurodegenerative pathology.
Anesthetic-induced neurotoxicity (AIN), particularly postoperative cognitive dysfunction and related perioperative neurocognitive disorders, remains a significant clinical challenge. Ferroptosis—an iron-dependent, lipid peroxidation-driven regulated cell death—has emerged as a key mechanism in preclinical models of anesthetic neurotoxicity. However, administration contexts (e.g., developmental, aged, spinal, or ototoxic) differ in patient populations, exposure paradigms, and tissue -specific outcomes. Preclinical evidence indicates that anesthetics like propofol, sevoflurane, and isoflurane trigger ferroptosis via iron dysregulation, antioxidant depletion, and lethal lipid peroxidation, contributing to neuronal injury and cognitive decline.Pharmacological inhibition of ferroptosis-associated pathways confers neuroprotection in these experimental models, although these findings remain strictly preclinical and do not establish clinical efficacy. This review first outlines core ferroptosis mechanisms, then details the distinct molecular pathways by which various anesthetics induce ferroptosis, and finally summarizes recent advances in ferroptosis-targeted neuroprotection. Crucially, all current evidence is derived exclusively from preclinical studies; clinical translation remains to be established. Moreover, ferroptosis’s relative contribution versus other cell death pathways likely varies across developmental stages, tissue types, and exposure conditions. Nonetheless, targeting ferroptosis represents a promising therapeutic strategy that warrants further investigation in well-designed translational studies to assess its potential for mitigating AIN across diverse clinical contexts. Targeting ferroptosis in anesthetic neurotoxicity: anesthetics trigger ferroptosis via iron overload, GPX4/GSH depletion, and lipid peroxidation, driving cognitive dysfunction. Pharmacological ferroptosis inhibition (e.g., Fer-1, Liproxstatin-1) blocks this cascade, offering neuroprotection against anesthetic-induced neurotoxicity.
Neurological complications are among typical clinical manifestations, both during the acute phase of SARS-CoV-2 infection and long-term post-acute COVID-19 sequelae, i.e., Long COVID. A growing body of evidence connects SARS-CoV-2 infection to systemic inflammation, peripheral immune dysregulation, functional alteration of the blood–brain barrier (BBB), neuroinflammatory processes, mitochondrial dysfunction and pathological protein aggregation, all of which are central to the pathogenesis of major neurodegenerative diseases. In this review, we discuss the converging shared underlying molecular mechanisms that link the ‘acute’ SARS-CoV-2 infection that often only lasts for days and ‘chronic’ neurodegenerative diseases that often take decades to develop. We further review human induced pluripotent stem cells (iPSCs)-derived brain organoid and BBB models for Parkinson’s disease (PD) and Alzheimer’s disease (AD) as well as artificial intelligence (AI)-facilitated knowledge graph methods that are used to hypothesize and validate the potential mechanistic links. We propose that besides the established links between viral infections and neurodegenerative or neuroinflammatory conditions, such as Epstein-Barr virus (EBV) in multiple sclerosis or herpes zoster in AD, SARS-CoV-2 infection might be another important factor driving the future burden of the most common neurodegenerative diseases.
Alzheimer’s disease (AD) has traditionally been framed as a neuronal disorder, yet white matter and myelin abnormalities are consistently detected in the preclinical period, before overt amyloid pathology or cognitive decline. This temporal relationship suggests that oligodendrocyte (OL) dysfunction acts upstream of, rather than downstream from, amyloid accumulation. In this review we argue that OL dysfunction and loss are a fundamental, mechanistically integrated component of AD pathogenesis, and we develop this argument as a single causal sequence. Central to it is the dual role of OLs in amyloid homeostasis: they express the complete amyloidogenic machinery and produce a quantitatively significant, comparatively aggregation-prone fraction of Aβ, while intact myelin is required for both axonal metabolic support and efficient Aβ clearance. A single lesion in the OL–myelin unit therefore simultaneously increases Aβ production and impairs its removal. We then examine why this lineage fails early: the exceptional metabolic and iron burden of myelin maintenance, combined with low glutathione reserves, renders OLs selectively vulnerable to oxidative injury and ferroptosis. This injury becomes self-sustaining through a metabolic–epigenetic feedback loop, diversion of finite microglial clearance toward myelin debris, and exhaustion of precursor-mediated repair, converting reversible injury into progressive myelin loss that further amplifies amyloid pathology. Together, these mechanisms define OL dysfunction as a self-reinforcing driver of AD and identify myelin preservation as a point of preventive leverage. Oligodendrocytes: A Stage-Dependent Node in Alzheimer’s Disease. Early responses proposed to be compensatory (left) may drift, beyond a tipping point, toward maladaptive amplification (right): oligodendrocytes both produce amyloid and, as myelin degrades, may contribute to amyloidogenic feedback and to a proposed metabolic–epigenetic loop that sustains progressive dysfunction. The strength and translational status of the individual mechanisms differ, ranging from direct human observations to causal mammalian experiments and exploratory non-mammalian findings
