Multi-dimensional early warning markers based on inflammatory factors, mitophagy-related molecules, epigenetic markers and nutritional exposure indicators, as well as potential intervention strategies such as nutritional supplementation, anti-inflammatory and pro-mitophagy targeting the above pathways were summarized, in order to provide a theoretical reference for the primary prevention of PD.
Abstract
Maternal high-fat diet (mHFD) is a growing global nutritional concern during pregnancy. It induces maternal systemic low-grade inflammation and oxidative stress, reshaping the intrauterine milieu via the placenta and causing selective developmental impairments in offspring midbrain dopaminergic (DA) neurons—including aberrant precursor proliferation/differentiation, simplified synapses, and nigrostriatal circuit deficits—which may increase adulthood Parkinson's disease (PD) susceptibility. Mechanistically, mHFD acts through two synergistic pathways: persistent activation of the insulin resistant–NF-κB inflammatory axis and suppression of PINK1/Parkin-mediated mitophagy, mutually reinforcing and compromising DA neuron resilience. This article reviews the pathological process of mHFD-mediated remodeling of the intrauterine microenvironment to increase the susceptibility of offspring PD and its two core mechanism pathways: the continuous activation of the IR-NF-κB inflammatory pathway and the functional inhibition of the PINK1/Parkin-mediated mitophagy pathway. On this basis, multi-dimensional early warning markers based on inflammatory factors, mitophagy-related molecules, epigenetic markers and nutritional exposure indicators, as well as potential intervention strategies such as nutritional supplementation, anti-inflammatory and pro-mitophagy targeting the above pathways were summarized, in order to provide a theoretical reference for the primary prevention of PD.
Pregnancy constitutes a critical window for fetal nervous system development. Maternal environmental exposure can trigger placenta-mediated intrauterine perturbations, exerting persistent programming effects on fetal neural development and elevating the susceptibility to neurodegenerative diseases in adulthood. This review systematically summarizes typical prenatal exposure types, including air pollutants, heavy metals, endocrine-disrupting chemicals, nutritional imbalance, and maternal stress. Focusing on four core mechanistic pathways—epigenetic modification, oxidative stress, neuroinflammation, and mitochondrial dysfunction—this study integrates epidemiological evidence, animal model data, and molecular mechanistic findings to elaborate how early-life environmental exposure reshapes neurodevelopmental trajectories and mediates long-term neurological damage. Notably, this review highlights the interactive feedback and cascade amplification effects among multiple biological mechanisms, and strictly distinguishes well-established causal associations from speculative inferences. This work constructs a stratified evidence framework for the developmental origin theory of neurodegenerative diseases, providing scientific support for precise pre-pregnancy and prenatal disease prevention and intervention strategies.
Jiajie Yu, Hong-mei Lian, Mengjiao Yang et al.· Frontiers in Public Health· 0 citations
Background/Objectives: The developmental origins of health and disease (DOHaD) theory suggests that intrauterine and early postnatal life represents a critical window for programming lifelong health trajectories and disease susceptibility in offspring. Maternal nutritional imbalance during this period is closely associated with obstetric complications and an elevated risk of metabolic disorders in children. As central metabolic hubs, mitochondria constitute a critical axis linking adverse in utero exposure to metabolic defects in offspring across generations. Methods: In this narrative review, we searched PubMed and Web of Science (up to 8 July 2026) for English-language literature linking maternal metabolic conditions and mitochondrial dysfunction. We included in vivo, in vitro, and clinical studies, explicitly excluding primary inherited mtDNA mutations and nonnutritional toxicant exposures to isolate nutritional programming effects. Results: Maternal metabolic stress induces multifaceted, tissue-specific mitochondrial alterations in the developing offspring. Rather than a uniform systemic decline, mitochondrial reprogramming exhibits profound spatial and cellular heterogeneity across critical metabolic organs, including the placenta, liver, skeletal muscle, heart, and hypothalamus. These developmental adaptations often manifest as molecular compensations, such as altered mitochondrial dynamics, perturbed biogenesis, and shifted OXPHOS capacity, ultimately leading to functional bioenergetic failure, oxidative stress, and the establishment of insulin resistance. Discussion: Organ-specific mitochondrial dysfunction drives the maternal transmission of metabolic syndrome. Targeting these mechanisms via dietary modifications, exercise, pharmacological agents, and mitochondrial transplantation offers promising strategies to rescue bioenergetics and prevent metabolic diseases in offspring.
Chuhan Shao, Hanmo Lin, Jie Yu et al.· Biomolecules· 0 citations
Background Oxidative stress and immune dysregulation are hallmark features of autism spectrum disorder (ASD), yet whether oxidative imbalance acts as an upstream trigger of immune activation remains unclear. The redox-sensitive transcription factor NFκB represents a potential mechanistic link. We investigated whether early-life oxidative stress contributes to persistent NFκB activation and neuroinflammation in ASD. Methods Umbilical cord blood and peripheral blood from ASD and typically developing children were analyzed for redox markers (GSH/GSSG ratio, malondialdehyde, 8-oxo-dG), NFκB activation (p65 DNA-binding and nuclear translocation), and inflammatory gene expression. The mechanistic relationship between oxidative stress and NFκB signaling was investigated in prenatal valproic acid (VPA)-exposed mice using antioxidant intervention (N-acetylcysteine, NAC), NFκB inhibition (Bay 11-7082), pro-oxidant challenge, behavioral assays, and primary amygdala neuron models. Results ASD children exhibited persistent oxidative imbalance detectable at birth, accompanied by increased NFκB activation and pro-inflammatory gene expression. VPA-exposed mice recapitulated these molecular and behavioral abnormalities. In primary neurons, oxidative stress directly enhanced NFκB activity and promoter binding, whereas antioxidant and mitochondrial-targeted approaches suppressed NFκB activation. Developmentally, oxidative stress preceded sustained NFκB activation, and prenatal, but not postnatal, NAC treatment prevented these abnormalities. NAC restored redox homeostasis, reduced NFκB signaling, and improved behavioral deficits, whereas NFκB inhibition alone attenuated inflammatory responses but failed to correct oxidative imbalance or behavioral abnormalities. Conclusion Early-life oxidative stress is an upstream pathogenic event associated with persistent NFκB activation and neuroinflammation in ASD. NFκB primarily mediates inflammatory signaling, while oxidative stress likely contributes to ASD-related behaviors through additional downstream pathways. These findings highlight early redox modulation as a potential therapeutic strategy.
Y. Jiao, Qingzheng Jia, Xiaozhuang Zhang et al.· Frontiers in Immunology· 0 citations
Major depressive disorder (MDD) and metabolic syndrome (MetS) frequently exhibit high comorbidity, with the latter characterized primarily by insulin resistance, dyslipidemia, and abdominal obesity. Growing evidence suggests that immune-inflammatory dysregulation constitutes a shared pathobiological basis for both conditions. This review focuses on the roles of innate and adaptive immune responses in this context, including glial cell activation, blood-brain barrier disruption, microglial polarization, and T/B cell functional imbalance, which collectively contribute to a systemic chronic low-grade inflammatory state. We further integrate the bidirectional regulatory effects of key immune signaling pathways—such as TLR4–NF-κB, PI3K–Akt–mTOR, and JAK–STAT—in central neuroinflammation and peripheral metabolic dysfunction. These intertwined mechanisms influence mood regulation and synaptic plasticity while exacerbating insulin resistance and lipid abnormalities. Additionally, we discuss the potential value of immune markers, including GFAP, CTRP3, IL-6, and IFN-γ, in disease subtyping and risk assessment, and evaluate the prospects of novel anti-inflammatory intervention strategies for precision therapy. Finally, we highlight the current limitations in translational research and advocate for systematically integrated multi-omics and longitudinal cohort studies to advance precise interventions and personalized management of depressive-metabolic comorbidity.
Xinxin Wang, Bo Zhang, Ran Xia et al.· Discover Neuroscience· 0 citations
Maternal immune activation (MIA) is associated with increased risk of neurodevelopmental disorders, including schizophrenia. Research demonstrates sex-specific responses to MIA, yet how MIA interacts with intrinsic sex differences during brain development remains unclear. Here, we investigated how poly(I:C)-induced MIA alters metabolic, epigenetic and inhibitory developmental trajectories. Female, but not male, poly(I:C) offspring exhibited an object location memory deficit, implicating the hippocampus as a vulnerable region. Using RNA sequencing of the prenatal hippocampus, we identified a pronounced female-specific transcriptional response to MIA, with enrichment of mitochondrial and chromatin-related pathways. Concurrently, intrinsic sex differences indicated divergent metabolic/mitochondrial maturation, such as increased expression of Ppargc1a (encoding peroxisome proliferator-activated receptor gamma coactivator 1-α) and increased antioxidant activity in females compared to males, consistent with greater metabolic capacity. MIA interacted with these trajectories, producing sex-dependent effects on mitochondrial dynamics which coincided with signatures of a more permissive chromatin state, including reduced histone deacetylase activity, increased histone acetylation and reduced H3K27 methylation. In adulthood, MIA offspring showed altered chloride transporter expression, with a shift toward NKCC1 (a molecular driver of the GABAergic switch) and evidence of promoter-level epigenetic regulation, most evident in females. This coincided with reduced clusters of the scaffolding protein gephyrin in adolescent poly(I:C) females, consistent with altered inhibitory synapse maturation. Together, these findings indicate that sex-specific metabolic programming shapes the neurodevelopmental response to MIA and contributes to the observed sex differences in brain and behavioural response. Understanding typical sex differences in mitochondrial development is critical for predicting vulnerability and informing therapeutic treatment.
Francesca McEwan, James Dal Santo, Chiho Kambara et al.· Brain, behavior, and immunit...· 0 citations
A marked reduction in estrogen levels during perimenopause substantially elevates the risk of Alzheimer’s disease (AD) and cognitive dysfunction in women. While the endocrine etiology is well established, applying this understanding to effective clinical prevention remains difficult. Recent findings of diminished cerebral glucose metabolism and lower mitochondrial cytochrome oxidase activity in menopausal women have shifted research attention toward mitochondrial homeostasis disruption and neuroimmune–inflammatory network imbalance as central mechanisms underlying menopausal cognitive decline. This article examines the characteristics and underlying mechanisms of mitochondrial and immune imbalances induced by estrogen withdrawal during menopause. Estrogen deficiency is shown to disrupt mitochondrial–immune homeostasis, particularly via ERβ-mediated mitochondrial oxidative phosphorylation system (OXPHOS) dysfunction and subsequent excessive activation of the NLRP3 inflammasome. The analysis further addresses enhanced inflammatory signaling resulting from excessive reactive oxygen species generation and mitochondrial DNA (mtDNA) release, as well as reduced synaptic plasticity due to impaired neurotransmitter synthesis and an inflammatory microenvironment. Additionally, the dysregulation of the estrogen-neuromodulatory system in menopausal cognitive decline is investigated. Recent studies demonstrate that intervention strategies targeting estrogen receptors, especially selective ERβ agonists, possess significant neuroprotective potential. Future approaches should incorporate biomarkers, including neuroimaging and genetic polymorphisms, to facilitate risk-stratified and individualized precision medicine. This integration may enhance the prevention or delay of menopause-associated cognitive decline in women.
tiantian qiu, Junying Zhang, Jiayou Zhao· International Journal of Mol...· 0 citations
