INTRODUCTION:Lithium manganate (LMO) is a new type of pollutant that is extensively applied in the manufacture of lithium-ion batteries. Accumulating evidence indicates that both manganese (Mn) and lithium (Li) can cross the blood-brain barrier and accumulate within the hippocampus. However, the neurotoxic effects of LMO on hippocampal core functions and the involved molecular mechanisms are still unclear. OBJECTIVES:This study observed whether LMO exposure impairs hippocampus-dependent learning and memory in mice and investigated related mechanisms and intervention strategies. METHODS:A whole-body inhalation exposure system was employed to simulate occupationally relevant in vivo exposure to LMO, with mice exposed to concentrations of 0, 1.35, 13.5, and 135 mg/m3 for 28 and 45 days, corresponding approximately to 3 and 5 human years. In parallel, in vitro co-exposure models were established using HT-22 cells and primary hippocampal neurons treated with Mn and Li. Neurobehavioral, neuropathological, live-cell imaging-based assays were used to assess learning and memory impairment, neuronal damage, and retrograde axonal transport dysfunction. RNA-sequencing and molecular biology approaches were conducted to explore and validate mechanisms. Mid1 silencing/knockdown and valproic acid (VPA) treatment were used to assess whether modulation of Mid1-related changes attenuates LMO-induced neurotoxicity. RESULTS:The results demonstrated that LMO exposure impaired learning and memory in mice. Mechanistically, LMO or Mn and Li co-exposure up-regulates the E3 ubiquitin ligase Mid1 which promotes the degradation of dynein light chain family members Dynlrb2 and Dynlt4 through the ubiquitin-proteasome pathway. This disruption impairs retrograde axonal transport in hippocampal neurons, resulting in neuronal injury and ultimately compromising learning and memory function in mice. Suppression of Mid1 ,or VPA treatment significantly improved the observed neuronal damage and the expression levels of factors related to axonal retrograde transport. CONCLUSION:This study indicates that LMO inhalation exposure is associated with learning and memory deficits and hippocampal neuronal injury, accompanied by Mid1-related ubiquitin-proteasome alterations and disrupted retrograde axonal transport.

Di(2-ethylhexyl) phthalate (DEHP), a widely utilized plasticizer, impairs male reproductive function; however, the precise mechanisms underlying this effect have yet to be fully elucidated. This study investigates DEHP-induced spermatocyte toxicity and identifies therapeutic strategies. Integrated network toxicology and proteomics delineated testicular toxicity mechanisms through multi-dimensional analyses. We demonstrate that DEHP exposure induces spermatocyte ferroptosis via PINK1/Parkin-mediated mitophagy. Mechanistically, the bioactive metabolite MEHP promotes NRF2 degradation through the ubiquitin-proteasome pathway, inducing excessive mitochondrial clearance. This process mediates mitochondrial Fe2+ efflux, causing iron dysregulation and lipid peroxidation. Pharmacological inhibition of mitophagy by CsA attenuated ferroptosis and restored iron homeostasis, confirming ferroptosis dependence on mitophagic activation. Crucially, NRF2 activation concurrently suppresses both mitophagic flux and ferroptotic execution. MEHP-induced NRF2 degradation initiates pathological mitophagy and facilitates mitochondrial iron efflux, resulting in dysregulated iron metabolism within spermatocytes. This cascade culminates in spermatocyte ferroptosis mediated by Fe2+ accumulation and lipid peroxidation. This work provides definitive evidence linking environmental toxicant-induced mitophagy to germ cell ferroptosis, identifies NRF2 as a central regulator of this pathway, and proposes targeted mitophagy inhibition combined with NRF2 stabilization as therapeutic interventions.

Nanoplastics are emerging environmental pollutants ubiquitously found in natural ecosystems. Although studies have shown that nanoplastics can accumulate in the testes of mice and affect spermatogenic cells, the specific toxicological mechanisms remain unclear. To investigate the specific mechanism by which polystyrene nanoplastics induce ferroptosis in mouse spermatocyte-derived GC-2spd(ts) cells and subsequently lead to male reproductive toxicity, this study exposed mouse germ cell lines (GC-1 spg and GC-2spd(ts)) to PS-NPs of two sizes (50 nm and 90 nm). Cell viability assays indicated that GC-2spd(ts) cells were more sensitive to PS-NPs exposure. Transcriptomic and proteomic analyses revealed that PS-NPs exposure induced intracellular reactive oxygen species (ROS) accumulation and significant alterations in related pathways, specifically activating the ferroptosis signaling pathway. Further mechanistic studies demonstrated that PS-NPs disrupted intracellular iron homeostasis, leading to the accumulation of labile Fe2+ , enhanced lipid peroxidation, depletion of the antioxidant glutathione, and mitochondrial dysfunction. At the molecular level, PS-NPs upregulated the expression of iron uptake-related proteins and significantly downregulated the iron exporter protein ferroportin1 (FPN1). In-depth investigation revealed that PS-NPs did not affect the transcriptional level of FPN1 but promoted FPN1 protein degradation by enhancing its ubiquitination modification, subsequently via the proteasome-dependent pathway. This process resulted in blocked cellular iron efflux, iron ion accumulation, and ultimately triggered ferroptosis. This study elucidates the molecular mechanism by which PS-NPs regulate FPN1 degradation through the ubiquitin-proteasome pathway, disrupt iron metabolic homeostasis, and thereby induce ferroptosis in germ cells, providing novel experimental evidence for assessing the male reproductive toxicity of nanoplastics.

Chemotherapy, while effective in targeting cancerous cells, often results in collateral damage to normal cells with high proliferative capacity, leading to iatrogenic ovarian injury. Ferroptosis has been implicated as a key driver of ovarian injury caused by chemotherapy drugs. However, the underlying molecular mechanisms remain incompletely understood. Therefore, this study was designed to elucidate the mechanism by which chemotherapy drugs induce ovarian injury through ferroptosis. Our findings demonstrate that the chemotherapeutic drug cyclophosphamide (CTX) impairs ovarian function and disrupts follicular development. Further analysis revealed characteristic features of ferroptosis within CTX-induced atretic follicular granulosa cells (GCs), including elevated Fe2+ accumulation, increased lipid peroxidation, and dysregulation of key ferroptosis-related molecules. Consistently, in vitro experiments demonstrated that treatment with the ferroptosis inhibitor Ferrostatin-1 (Fer-1) significantly alleviated CTX-induced cytotoxicity in KGN cells. Moreover, using the iron chelator deferoxamine (DFO) and the iron supplement ferric ammonium citrate (FAC), we demonstrated that modulating iron homeostasis could attenuate or aggravate CTX-induced ferroptosis in GCs, thereby confirming that disrupted iron homeostasis is a primary trigger for CTX-induced ferroptosis in GCs. Notably, we observed that Fe2+ accumulation occurred within mitochondria and subsequently triggered excessive mitophagy. This heightened mitophagy response exacerbated mitochondrial damage, thereby establishing a vicious cycle of persistent mitochondrial impairment that ultimately sensitized GCs to ferroptosis. Conversely, treatment with the mitophagy inhibitor cyclosporin A (CSA) alleviated CTX-induced ferroptosis in GCs. In conclusion, our study reveals that mitophagy-mediated ferroptosis is a critical mechanism underlying CTX-induced ovarian injury. These findings suggest that therapeutic strategies targeting mitophagy or ferroptosis hold promise for the treatment and prevention of chemotherapy-associated ovarian toxicity.

The precise antiviral mechanism of manganese ions (Mn²⁺) remains incompletely understood. In this study, we elucidated how Mn²⁺ counteracts highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) infection and defined its link to the NF-κB signaling pathway. First, we determined that 10 µM MnCl₂ was the maximum non-toxic dose on Marc-145 cells. Pretreatment with MnCl₂ at this dose before HP-PRRSV infection significantly inhibited viral replication, as evidenced by reduced viral titers and viral N protein expression, while also alleviating cytopathic effects and downregulating the secretion of pro-inflammatory cytokines IL-6 and IL-8. Mechanistically, HP-PRRSV infection suppressed the activation of the NF-κB pathway, indicated by decreased phosphorylation levels of p65 and IκBα. MnCl₂ pretreatment effectively reversed this suppression. Furthermore, it concurrently upregulated the expression of antiviral interferons, IFN-α and IFN-β. Crucially, functional validation using the specific NF-κB agonist Diproqualone (Dip-1) mimicked the antiviral effect of Mn²⁺, whereas inhibition of the pathway with BAY 11-7082 exacerbated infection and suppressed interferon production. Collectively, these findings demonstrate that manganese antagonizes HP-PRRSV infection by activating the NF-κB signaling pathway, which in turn induces a potent interferon response.

Oxidative stress and neuroinflammation are two key pathological features in the early stage of Alzheimer's disease (AD), and they promote each other to further drive the progression of AD. Therefore, the development of therapeutic agents with dual anti-inflammatory and antioxidant properties represents a promising strategy for AD treatment. C66, a synthetic derivative of curcumin, protected PC12 cells and primary neurons from oxidative damage caused by Aβ. In addition, C66 alleviated Aβ-induced excessive inflammatory response in BV2 cells. Further results showed that C66 reduced neuroinflammation and neuronal apoptosis, ultimately improved cognitive decline in APPswe/PSEN1dE9 (APP/PS1) double transgenic AD mice. Importantly, C66 exhibited superior improved properties in APP/PS1 mice compared with the clinical control drug donepezil. Mechanistically, we indicated that C66 conferred its neuroprotective effects by inhibiting c-Jun N-terminal kinase (JNK) pathway. The result was further confirmed by using SP600125, a specific JNK inhibitor. Together, our findings suggest that C66 is expected to be further developed as a drug candidate for AD therapy.

Overexposure manganese can induce neurotoxicity and apoptosis, in addition, miRNAs are widely involved in the apoptotic process of neurons. Therefore, it is crucial to explore the mechanism of miRNAs in manganese-induced neuronal apoptosis and then to find potential targets. Our present study showed that miR-143 expression was increased in striatum after exposure high doses of manganese. Then, we upregulated miR-143 expression via stereotaxic, and overexpression of miR-143 promoted apoptosis in striatal neurons. Further studies showed a negative regulatory relationship between miR-143 and ERK5, miR-143 upregulation decreased ERK5 mRNA level, inhibiting ERK5 signaling pathway, increasing the expression of Bax and Caspase-3, and exacerbating the apoptosis of striatal neurons. In conclusion, these results suggest that overexpression of miR-143 inhibited the ERK5 signaling pathway and promoted manganese-induced apoptosis in striatal neurons.

Parkinson's disease (PD) is a severe neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons. Emerging evidence suggests that deubiquitinating enzymes (DUBs), which regulate protein homeostasis through the cleavage of ubiquitin chains, play critical roles in PD pathogenesis. In this study, we discovered that a DUB, ovarian tumor deubiquitinase 6A (OTUD6A), was significantly upregulated in both PD patients and PD mouse models. Notably, OTUD6A deficiency effectively protected dopaminergic neurons from degeneration and improved motor deficits in both acute and chronic PD mouse models. Through comprehensive mass spectrometry analysis and co-immunoprecipitation assays, we identified that actin gamma 1 (ACTG1) serves as a key substrate of OTUD6A. Mechanistically, OTUD6A specifically interacts with the 8-181 aa domain of ACTG1 and preferentially cleaves K48-linked polyubiquitin chains, thereby enhancing ACTG1 protein stability in neuronal cells. The stabilized ACTG1 subsequently binds to p53 and facilitates its nuclear translocation, leading to the transcriptional activation of pro-apoptotic genes and promoting neuronal apoptosis. Collectively, our findings demonstrate that OTUD6A promotes dopaminergic neuron degeneration and PD progression by deubiquitinating and stabilizing ACTG1, which in turn activates a p53-dependent apoptotic pathway. These findings identify OTUD6A as a potential therapeutic target for PD intervention.

Sepsis induced acute liver injury (SALI), is a type of acute and severe disease that is generally characterized by producing significant amounts of reactive oxygen species (ROS) in liver tissue, and in response to excessive ROS, producing huge amounts of inflammatory factors by hepatocytes. Considering the crucial role of ROS in SALI, a Pd doped CeO 2 (CP) nano‐heterojunction with enhanced ROS scavenging capacity is developed to act as a catalytic nanomedicine for the treatment of SALI. Combining with near infrared (NIR) irradiation, it exhibits excellent scavenging capacity of ROS including hydroxyl radical (•OH), superoxide anion (•O 2 − ), as well as singlet oxygen ( 1 O 2 ) for CP. Significantly, it also demonstrates the excellent antioxidant and anti‐inflammatory activities for lipopolysaccharides (LPS) stimulated macrophages (RAW264.7), and cecum ligation and puncture (CLP) treated C57BL/6J mice via reducing intracellular ROS levels, decreasing inflammatory factors expression levels, as well as activating Keap1/Nrf‐2/HO‐1 pathway to reprogram redox homeostasis, induce cellular autophagy, reduce systemic inflammation and promote liver tissue repair, finally achieving the alleviation of SALI. It provides a promising therapeutic strategy of CP+NIR with high efficacy and biosafety for the management of SALI.

Nanoplastics (NPs) pollution has become a pressing global environmental issue. NPs possess the ability to adsorb heavy metals, thereby acting as vectors that facilitate the entry of these toxic substances into living organisms. However, the synergistic toxic effects of NPs and heavy metals, particularly with regard to male reproductive health, remain poorly understood. This study establishes in vivo and in vitro models to assess the effects of single and co-exposure to polystyrene nanoplastics (PS-NPs, 0.1 μm) and manganese (Mn) on male reproductive function. Our results reveal that co-exposure leads to a synergistic toxic effect, aggravating testicular damage, sperm abnormalities, and hormone disruption. Mechanistically, PS-NPs and Mn collaboratively suppress the RNA-binding protein YTHDC2, which in turn impairs Mdm2 transcription and translation in an m6A-dependent manner. This disruption results in cell cycle arrest via the Mdm2-p53 pathway, ultimately hindering spermatogenesis. Notably, baicalin, a natural compound, effectively targets YTHDC2 and mitigates the reproductive toxicity induced by co-exposure. These findings provide the novel evidence of the synergistic reproductive toxicity of PS-NPs and Mn in male mammals, offering new insights into their combined toxic effects and highlighting the potential of baicalin as a therapeutic intervention.

Male infertility, as a globally significant reproductive health issue, remains idiopathic in over 40% of cases. Reproductive disorders in males induced by environmental pollutants, such as di(2-ethylhexyl) phthalate (DEHP), have garnered considerable attention in recent years. DEHP induces testicular oxidative stress and ferroptosis via its active metabolite MEHP, thereby leading to spermatogenic dysfunction. Lycium barbarum polysaccharide (LBP), a traditional food and medicine homologous substance, exhibits potential antioxidant and reproductive protective properties. However, the underlying mechanism by which LBP intervenes in the toxicity induced by DEHP remains to be elucidated. This study explored the protective effect and molecular mechanism of LBP on DEHP-induced testicular injury through in vivo and in vitro experiments. The result showed that DEHP exposure (150 mg/L in free drinking water for 6 weeks) significantly decreased testicular weight, sperm concentration, and sperm motility in mice, while DEHP exposure induced pathological damage to testicular tissue, as evidenced by cavitation of seminiferous tubules, reduced numbers of spermatocytes, and vacuolar degeneration of Sertoli cells. However, LBP (450 mg/L) treatment significantly reversed testicular damage and sperm parameters. In vitro, MEHP reduced the viability of GC2 cells (spermatocyte cell line) and TM4 cells (Sertoli cell line), and LBP significantly restored cell activity. Mechanistically, exposure to DEHP/MEHP results in iron overload (elevated levels of free Fe2+), lipid peroxidation (increased MDA and reduced GSH), and dysregulated expression of key proteins involved in ferroptosis and iron homeostasis within the testis and cells. Furthermore, it was demonstrated that when NRF2 was specifically inhibited by ML385 or silenced via siRNA, the protective effects of LBP were abrogated, thereby validating the critical role of NRF2 in the regulation of iron homeostasis by LBP. In conclusion, LBP mitigates DEHP-induced testicular injury by activating NRF2 to regulate iron homeostasis in Sertoli cells and spermatocytes cells. This study not only offers a potential strategy for the prevention and treatment of male reproductive disorders caused by DEHP exposure, but also underscores the reproductive protective effects and application prospects of LBP in this context.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the pathological accumulation of α-synuclein aggregates and the selective degeneration of dopaminergic neurons in the substantia nigra. Growing evidence implicates dysfunction of the ubiquitin-proteasome system (UPS), a critical regulator of protein homeostasis, in the pathogenesis of PD through impaired clearance of toxic protein species. As key components of the UPS, deubiquitinating enzymes (DUBs) counterbalance ubiquitin ligase activity by cleaving ubiquitin chains from substrate proteins, thereby playing pivotal roles in maintaining protein turnover and regulating cellular signaling pathways. Notably, emerging research has demonstrated that specific DUBs are intimately involved in modulating multiple PD-related pathological processes, including α-synuclein aggregation, mitochondrial oxidative stress, iron homeostasis, and neuronal survival. These findings suggest DUBs as promising therapeutic targets for PD intervention. This review comprehensively summarize the pathophysiological roles of PD-associated DUBs, their molecular mechanisms in disease progression, and recent advances in the development of DUB inhibitors as potential disease-modifying therapies for PD.

Breast cancer, as a highly prevalent malignant tumor among women, has a consistently high mortality rate due to metastasis and drug resistance. Lycium barbarum polysaccharides (LBP), which have been reported to have significant anti-tumor activity, have not yet had their molecular mechanism and signaling pathways against breast cancer clearly defined. In this study, the CCK-8 experiment determined that 8 mg/mL LBP treatment for 48 h was the optimal condition for subsequent transcriptomics and metabolomics analyses. The results demonstrated that a high concentration of LBP significantly reduced the viability of MCF-7 cells and inhibited cell proliferation. Transcriptome sequencing revealed that LBP markedly altered the expression levels of the genes HO-1, FTH1, FTL, and TFRC. Metabolomics analysis further indicated that LBP significantly impacted glutathione metabolism, glycerophospholipid metabolism, and the alanine-aspartate-glutamate metabolic pathway. Further integration of transcriptomic and metabolomic data suggests that LBP may suppress cell proliferation by activating the ferroptosis pathway via the NRF2/HO-1 axis. To further validate this hypothesis, we conducted additional experiments to detect the NRF2/HO-1 signaling pathway and markers associated with ferroptosis. The results demonstrated that LBP treatment significantly upregulated the expression of NRF2 and its downstream effector molecule HO-1. Moreover, the specific NRF2 inhibitor ML385 was able to reverse the alterations in GSH, Fe2+, and MDA levels induced by LBP. In conclusion, our research results indicate that LBP induces ferroptosis by activating the NRF2/HO-1 signaling pathway.

A growing body of systematic reviews and meta-analyses has suggested connections between exposure to heavy metals and cognitive impairments. However, there is a lack of comprehensive synthesis and credibility grading. We conducted a synoptic review to synthesize these findings and reveal current research gaps. Through the evaluation of the overall quality of evidence and group analysis, the strength of association in different scenarios is clarified. An extensive literature search was conducted across PubMed, Web of Science, and Embase from their inception to July 16, 2024. The methodological quality was assessed by the A Measurement Tool to Assess Systematic Reviews (AMSTAR), and the strength of the evidence was evaluated based on the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. A total of 20 eligible studies encompassing 83 meta-analyses and examining 10 heavy metals (manganese, lead, copper, mercury, zinc, iron, cadmium, chromium, antimony, and nickel) were included. The average AMSTAR score was 8.23, indicating moderate methodological quality. 17 meta-analyses were rated as providing moderate to high-quality evidence according to GRADE. Among these, essential metals such as Mn (hair, drinking water, and air) and Cu (blood) show positive correlations with CI, while Zn (blood) demonstrate a negative correlation. Non-essential metals including Pb (blood and hair) and Hg (long-term low-dose exposure) exhibit positive correlations with CI. In summary, our findings highlight the complex heavy metal exposure and cognitive function. This synthesis contributes to a clearer understanding of the existing evidence and helps reconcile discrepancies in previous research.

The expansive surface area of microplastics (MPs) allows them to retain pollutants; however, the combined toxicity of mixed MPs and organic contaminants remains poorly studied. The semen quality of men worldwide was observed to exhibit downward trends. This study investigates the reproductive toxicity and underlying mechanisms of male mice exposed to MPs and a novel brominated flame retardant, decabromodiphenyl ethane (DBDPE), individually or combined. Male mice were treated by oral gavage with corn oil, 5 or 50 mg/kg DBDPE, 10 mg/kg MPs [a mixture of PE (polyethylene) and PVC (polyvinyl chloride)], and DBDPE + MPs (50 mg/kg DBDPE mixed with 10 mg/kg MPs) for 7 weeks. Our results suggested that DBDPE alone decreased the sex hormone levels and sperm count, whereas MPs alone had no significant effect. DBDPE and/or MPs impaired testicular morphology, sperm malformation rate, oxidative stress levels, and apoptosis. Our results of transcriptomics from GC-2 cells indicated that DBDPE and MPs lead to changes in oxidative stress, apoptosis, inflammation, proliferation, and differentiation. Furthermore, DBDPE and/or MP exposure inhibited the Kelch-like ECH-associated protein 1- NF-E2-related factor 2 (Keap1-Nrf2) signaling pathway. Moreover, the combined treatment of MPs and DBDPE exerted an antagonistic effect on the reproductive system of mice. This study provides valuable insights into the mechanisms of joint action in reproductive toxicity in mammals due to the combined exposure to MPs and DBDPE.

Arsenic (As) is recognized as a potent environmental contaminant associated with bladder carcinogenesis. However, its molecular mechanism remains unclear. Metabolic reprogramming is one of the hallmarks of cancer and is as a central feature of malignancy. Here, we performed the study of cross-talk between the mammalian target of rapamycin complex 1 (mTORC1)/ Hypoxia-inducible factor 1 alpha (HIF-1α) pathway and aerobic glycolysis in promoting the proliferation and migration of bladder epithelial cells treated by arsenic in vivo and in vitro. We demonstrated that arsenite promoted N-methyl-N-nitrosourea (MNU)-induced tumor formation in the bladder of rats and the malignant behavior of human ureteral epithelial (SV-HUC-1) cell. We found that arsenite positively regulated the mTORC1/HIF-1α pathway through glucose transporter protein 1 (GLUT1), which involved in the malignant progression of bladder epithelial cells relying on glycolysis. In addition, pyruvate kinase M2 (PKM2) increased by arsenite reduced the protein expressions of succinate dehydrogenase (SDH) and fumarate hydratase (FH), leading to the accumulation of tumor metabolites of succinate and fumarate. Moreover, heat shock protein (HSP)90, functioning as a chaperone protein, stabilized PKM2 and thereby regulated the proliferation and aerobic glycolysis in arsenite treated SV-HUC-1 cells. Taken together, these results provide new insights into mTORC1/HIF-1α and PKM2 networks as critical molecular targets that contribute to the arsenic-induced malignant progression of bladder epithelial cells.

Manganese (Mn) induced learning and memory deficits through mechanisms that are not fully understood. In this study, we discovered that the demethylase FTO was significantly downregulated in hippocampal neurons in an experimental a mouse model of Mn exposure. This decreased expression of FTO was associated with Mn-induced learning and memory impairments, as well as the dysfunction in synaptic plasticity and damage to regional neurons. The overexpression of FTO, or its positive modulation with agonists, provides protection against neurological damage and cognitive impairments. Mechanistically, FTO interacts synergistically with the reader YTHDF3 to facilitate the degradation of GRIN1 and GRIN3B through the m6A modification pathway. Additionally, Mn decreases the phosphorylation of SOX2, which specifically impairs the transcriptional regulation of FTO activity. Additionally, we found that the natural compounds artemisinin and apigenin that can bind molecularly with SOX2 and reduce Mn-induced cognitive dysfunction in mice. Our findings suggest that the SOX2-FTO-Grins axis represents a viable target for addressing Mn-induced neurotoxicity and cognitive impairments.

The nervous system interacts with the immune system through a variety of cellular regulators, signaling pathways, and molecular mechanisms. Disruptions in these interactions lead to the development of multiple neurological diseases. Recent studies have identified that specialized pro-resolving mediators (SPMs) play a regulatory role in the neuroimmune system. This study reviews recent research on the function of SPMs in the inflammatory process and their association with the nervous system. The review aims to provide new perspectives for studying the pathogenesis of neurological diseases and identify novel targets for clinical therapy.

Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role in regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable in vital life processes such as cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, a sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key processes like mitochondrial biogenesis, mitochondrial dynamics, and mitophagy, which have garnered increasing attention from researchers to unveil their specific molecular mechanisms. In this review, we present a comprehensive summary of the primary mechanisms and functions of key regulators involved in major components of MQC. Furthermore, the critical physiological functions regulated by MQC and its diverse roles in the progression of various systemic diseases have been described in detail. We also discuss agonists or antagonists targeting MQC, aiming to explore potential therapeutic and research prospects by enhancing MQC to stabilize mitochondrial function.

BACKGROUND:Understanding the molecular mechanisms of Alzheimer's disease (AD) has important clinical implications for guiding therapy. Impaired amyloid beta (Aβ) clearance is critical in the pathogenesis of sporadic AD, and blood monocytes play an important role in Aβ clearance in the periphery. However, the mechanism underlying the defective phagocytosis of Aβ by monocytes in AD remains unclear.METHODS:Initially, we collected whole blood samples from sporadic AD patients and isolated the monocytes for RNA sequencing analysis. By establishing APP/PS1 transgenic model mice with monocyte-specific cystatin F overexpression, we assessed the influence of monocyte-derived cystatin F on AD development. We further used a nondenaturing gel to identify the structure of the secreted cystatin F in plasma. Flow cytometry, enzyme-linked immunosorbent assays and laser scanning confocal microscopy were used to analyse the internalization of Aβ by monocytes. Pull down assays, bimolecular fluorescence complementation assays and total internal reflection fluorescence microscopy were used to determine the interactions and potential interactional amino acids between the cystatin F protein and Aβ. Finally, the cystatin F protein was purified and injected via the tail vein into 5XFAD mice to assess AD pathology.RESULTS:Our results demonstrated that the expression of the cystatin F protein was specifically increased in the monocytes of AD patients. Monocyte-derived cystatin F increased Aβ deposition and exacerbated cognitive deficits in APP/PS1 mice. Furthermore, secreted cystatin F in the plasma of AD patients has a dimeric structure that is closely related to clinical signs of AD. Moreover, we noted that the cystatin F dimer blocks the phagocytosis of Aβ by monocytes. Mechanistically, the cystatin F dimer physically interacts with Aβ to inhibit its recognition and internalization by monocytes through certain amino acid interactions between the cystatin F dimer and Aβ. We found that high levels of the cystatin F dimer protein in blood contributed to amyloid pathology and cognitive deficits as a risk factor in 5XFAD mice.CONCLUSIONS:Our findings highlight that the cystatin F dimer plays a crucial role in regulating Aβ metabolism via its peripheral clearance pathway, providing us with a potential biomarker for diagnosis and potential target for therapeutic intervention.