The abnormal accumulation of damaged mitochondria severely impedes tissue repair, and conventional therapeutic approaches, such as drug treatments, are often ineffective to remove damaged mitochondria. In this study, we developed gene-engineered aligned electrospun fibers by integrating microfluidic chip technology with a micro-sol oriented electrospinning technique. This study is the first to demonstrate the repair of damaged fascia by promoting mitocytosis through upregulating tetraspanin-9 (TSPAN9). The key gene for mitochondrial exocytosis, TSPAN9, was initially encapsulated into liposomes using microfluidic chip technology. Subsequently, core-shell structured aligned electrospun fibers were fabricated via oriented micro-sol electrospinning, where TSPAN9-loaded liposomes were protected by hyaluronic acid (HA) in the core layer, while aligned polylactic acid (PLA) fibers formed the outer shell layer. In vitro studies revealed that the aligned fibers closely mimicked the oriented structure of fascia tissue and significantly enhanced cell migration by providing directional physical cues. By sustained release of gene-loaded liposomes into cells, mitochondrial homeostasis was effectively restored, mitochondrial respiration was recovered, reactive oxygen species levels were reduced, and mitochondrial membrane potential was maintained. In vivo studies confirmed that these gene-engineered fibers effectively suppressed inflammatory responses and promoted fascia regeneration by facilitating the removal of damaged mitochondria through mitocytosis. In conclusion, gene-engineered fibers developed in this study, which enhance mitocytosis, offer a novel and promising therapeutic strategy for fascia tissue repair.

In recent years, there has been increasing interest in utilizing fish cell culture in vitro assays, as alternatives to whole fish assays, for assessing the toxicity of aquatic pollutants. The fish cell line RTL-W1, derived from rainbow trout (Oncorhynchus mykiss) liver, was shown to retain several tissue specific features and to respond to chemical insults similarly to fish in vivo. In our study, we investigated the toxicity of two metals silver and cadmium and two pesticides azoxystrobin and paraquat using a cytotoxicity assay that measures simultaneously cell metabolic activity and cell membrane integrity. Moreover, we developed a novel 'high-content imaging' approach to evaluate if mitochondria's surface area is a sensitive and specific indicator of mitochondria toxicity. Initially, the cytotoxicity assay was used to determine the chemicals' effective concentrations (EC50). Subsequently, we assessed the mitochondria surface area at different toxicity level (i.e., EC50, EC25 and EC10) to compare the sensitivity and specificity of this method. The EC50s measured by cell metabolic activity, for silver, cadmium, azoxystrobin and paraquat were 0.71, 29.05, 2.34 and 1260 μM, respectively. Mitochondria surface area was reduced by all chemicals at the EC50, and by silver and azoxystrobin at the EC10 and EC25; indicating that the latter chemicals affect mitochondria more specifically. In conclusion, our study demonstrated that mitochondrial surface area serves as a sensitive marker for chemicals inducing mitochondria toxicity in fish liver cells. Additionally, assays using RTL-W1 cells proved to be effective for detecting the hepatic cytotoxicity of environmental contaminants.

Realgar is a toxic mineral medicine containing arsenic that is present in many traditional Chinese medicines. It has been reported that the abuse of drugs containing realgar has potential neurotoxicity, but its mechanism of toxicity has not been fully clarified. In this study, we demonstrated that arsenic in realgar promoted mitochondrial fission via UBXD8-mediated DRP1 translocation to the mitochondria and activated mitophagy via PINK1-Parkin, resulting in mitochondrial dysfunction and nerve cell death in the rat cortex. We used PC12 cells and treated them with inorganic arsenic (iAs). Mdivi-1, a mitochondrial fission inhibitor, and the siRNA UBXD8 or PINK1 were used as interventions to verify the precise mechanism by which arsenic affects realgar-induced mitochondrial instability. The results revealed that the arsenic in realgar accumulated in the brain and led to neurobehavioral abnormalities in the rats. We demonstrated that arsenic in realgar-induced high expression of UBXD8 promoted the translocation of DRP1 to the mitochondria, where it underwent phosphorylation, which led to the over-fission of the mitochondria and mitochondria-mediated apoptosis. Moreover, the over-fission of the mitochondria activates mitophagy, which is self-protective but only partially alleviates apoptosis and mitochondria dysfunction. Our findings revealed the crosstalk between mitochondrial fission and mitophagy in realgar-induced neurotoxicity. These results highlight the role of the transposition of DRP1 by UBXD8 in realgar-induced mitochondrial dysfunction and provide new ideas and data for the study of the mechanism of realgar-induced neurotoxicity.

Reperfusion through thrombolytic therapy or primary percutaneous coronary intervention is commonly used to deal with acute myocardial infarction. However, the reperfusion procedure is accompanied by myocardial ischemia-reperfusion injury (MIRI). Currently, there is no therapeutics that can effectively deal with MIRI in clinical practice. Herein, the potential of ceria nanoparticles (CNPs) coated by different ligands in the treatment of rat MIRI is evaluated. The results demonstrate that CNPs can effectively modulate the oxidative stress in the heart tissue through the elimination of reactive oxygen species (ROS) and stimulation of endogenous antioxidant system. The inhibition of oxidative stress results in the reduction of p-Drp1 (Ser 616) which is critical in driving the fission and fragmentation of mitochondria. The improved mitochondrial dynamics saves the cardiomyocytes from apoptosis and reduces the acute injury of left ventricular wall during the MIRI. The ejection function of the left ventricle for both the short-term and long-term MIRI rats is well preserved. We therefore believe based on these results that the administration of CNPs is beneficial in the attenuation of MIRI during the acute stage. These findings provide useful information for the future fabrication of inorganic antioxidant nanomedicine for the treatment of MIRI.

Mitochondria, essential organelles responsible for cellular energy production, emerge as a key factor in the pathogenesis of neurodegenerative disorders. This review explores advancements in mitochondrial biology studies that highlight the pivotal connection between mitochondrial dysfunctions and neurological conditions such as Alzheimer's, Parkinson's, Huntington's, ischemic stroke, and vascular dementia. Mitochondrial DNA mutations, impaired dynamics, and disruptions in the ETC contribute to compromised energy production and heightened oxidative stress. These factors, in turn, lead to neuronal damage and cell death. Recent research has unveiled potential therapeutic strategies targeting mitochondrial dysfunction, including mitochondria targeted therapies and antioxidants. Furthermore, the identification of reliable biomarkers for assessing mitochondrial dysfunction opens new avenues for early diagnosis and monitoring of disease progression. By delving into these advancements, this review underscores the significance of understanding mitochondrial biology in unraveling the mechanisms underlying neurodegenerative disorders. It lays the groundwork for developing targeted treatments to combat these devastating neurological conditions.

Mitochondria are central to cellular energy production, and their dysfunction is a major contributor to oxidative stress and chronic inflammation, pivotal factors in aging, and related diseases. With aging, mitochondrial efficiency declines, leading to an increase in ROS and persistent inflammatory responses. Therapeutic interventions targeting mitochondrial health show promise in mitigating these detrimental effects. Antioxidants such as MitoQ and MitoVitE, and supplements like coenzyme Q10 and NAD + precursors, have demonstrated potential in reducing oxidative stress. Additionally, gene therapy aimed at enhancing mitochondrial function, alongside lifestyle modifications such as regular exercise and caloric restriction can ameliorate age-related mitochondrial decline. Exercise not only boosts mitochondrial biogenesis but also improves mitophagy. Enhancing mitophagy is a key strategy to prevent the accumulation of dysfunctional mitochondria, which is crucial for cellular homeostasis and longevity. Pharmacological agents like sulforaphane, SS-31, and resveratrol indirectly promote mitochondrial biogenesis and improve cellular resistance to oxidative damage. The exploration of mitochondrial therapeutics, including emerging techniques like mitochondrial transplantation, offers significant avenues for extending health span and combating age-related diseases. However, translating these findings into clinical practice requires overcoming challenges in precisely targeting dysfunctional mitochondria and optimizing delivery mechanisms for therapeutic agents. Continued research is essential to refine these approaches and fully understand the interplay between mitochondrial dynamics and aging.

Cadmium (Cd) is a persistent environmental heavy metal pollutant that has been an important issue in toxicology research worldwide. This toxic element is non-degradable and accumulates indefinitely in the ecosystem, and gradually accumulates in living organisms through nutrient transfer, ultimately posing a significant risk to the health of animals. The hepatic system is both the main target organ for Cd bioaccumulation and the metabolic center of organisms, and is particularly susceptible to heavy metal exposure. However, the underlying mechanism of whether LBP protects against Cd-induced liver injury in male Shaoxing ducks is still unknown. In our study, male Shaoxing ducks were treated with Cdcl2 (50 mg/kg) and/or LBP (50 mg/kg) for 30 days. We found that Cd exposure reduced the growth rate, feed intake, liver weight and organ index, and increased the serum biochemical indexes (AST, ALT, ALP) in Shaoxing ducks. Further studies have shown that Cd induces liver pathological damage and macro/trace element metabolism disorders, thereby inhibiting the activity of Nrf2 antioxidant signaling pathway and further inducing oxidative stress. Finally, we found that Cd induces the destruction of liver mitochondrial structure, disrupts the normal mitochondrial biogenesis and fusion/fission disorder, and thus causes liver pyroptosis and fibrosis. In this process, we found that LBP administration significantly improved Cd-induced growth inhibition and liver damage.

Environmental metal mixtures can cause combined neurotoxicity, but the underlying mechanism remains unclear. Mitochondria are crucial for energy metabolism in the nervous system, and their dysfunction leads to neurodegeneration. Zinc (Zn) is a coenzyme of many mitochondrial enzymes that controls mitochondrial function. This study investigated the role of Zn in the neurotoxicity induced by Mn + Pb and Pb + As mixtures. Zn supplementation improved the survival rate and learning ability of Caenorhabditis elegans following their exposure to mixtures of Mn + Pb and Pb + As by enhancing their mitochondrial morphology, membrane potential, and respiratory chain. Similarly, in HT22 cells, Zn mitigated the decrease in cellular activity and increase in apoptosis induced by the Mn + Pb and Pb + As mixtures by improving mitochondrial morphology and function. Mechanistically, Zn activated the PINK1 and MFN-2/OPA-1 pathways, promoting mitophagy and mitochondrial fusion. However, inhibition of mitophagy reversed the protective effect of Zn, indicating its reliance on mitophagy for neuroprotection. Our study demonstrated that Zn alleviates the combined neurotoxicity of Mn + Pb and Pb + As mixtures by enhancing mitophagy and mitochondrial fusion, suggesting that Zn supplementation is a potential treatment for metal-induced neurotoxicity.

Mitochondrial dysfunction is a known contributor to subarachnoid haemorrhage (SAH) induced early brain damage (EBI), leading to poor neurological outcomes. An experimental SAH model was induced in adult male Wistar rats using endovascular perforation. Donepezil, an acetylcholinesterase (AChE) inhibitor (1 or 2 mg/kg body weight), was administered intraperitoneally 4 h after SAH. The severity of cerebral cortex injury was assessed using blood clot grading, behavioral tests and H and E staining. We carried out an assessment of neuroinflammatory markers using western blotting and immunofluorescence. Additionally, we examined neuronal architecture using H and E staining, measured mitochondrial redox imbalance or ROS and membrane potential (Δѱm) and analyzed mitochondrial morphology using transmission electron microscopy (TEM). Apoptotic markers and mitochondrial respiratory complexes were assessed by western blotting. Our results indicated that donepezil treatment significantly upregulated PSD95, α7-AChR, CaMKII, BDNF, CREB, and PI3K expression in cerebral cortical neurons in response to SAH. This was accompanied by improved neurological function, reduced brain edema, decreased neuronal degeneration, and increased levels of OXPHOS and ATP. In the cerebral cortex, donepezil inhibited mitochondria-associated neuronal apoptosis after SAH as revealed by increased membrane potential integrity of mitochondria, reducing the ratio of Bax to Bcl-2 and inhibiting caspase-3 activity. Additionally, donepezil upregulated synaptic proteins (PSD95), strengthening synaptic connections and supporting spatial working memory circuits via the neurotrophic factor BDNF in post-SAH rats. Our research concludes that donepezil has neuroprotective benefits by inhibiting SAH-induced mitochondrial-mediated cell death through the regulation of Drp1-mediated mitochondrial morphology changes.

The incidence of vascular dementia (VaD), as one of the main types of dementia in old age, has been increasing year by year, and exploring its pathogenesis and seeking practical and effective treatment methods are undoubtedly the key to solving this problem. Phosphoglycerate translocase 5 (PGAM5), as a crossroads of multiple signaling pathways, can lead to mitochondrial fission, which in turn triggers the onset and development of necroptosis, and thus PGAM5 may be a novel target for the prevention and treatment of vascular dementia.

Animal model of vascular dementia was established by Two-vessel occlusion (2-VO) method, and cellular model of vascular dementia was established by oxygen glucose deprivation (OGD) method. Neuronal damage was detected in vivo and in vitro in different groups using different concentrations of the PGAM5-specific inhibitor LFHP-1c, and necroptosis and mitochondrial dynamics-related factors were determined.

In vivo experiments, 10 mg/kg-1 and 20 mg/kg-1 LFHP-1c improved cognitive deficits, reduced neuronal edema and vacuoles, increased the number of nissl bodies, and it could modulate the expression of Caspase family and Bcl-2 family related proteins and mRNAs and ameliorate neuronal damage. Simultaneously, in vitro experiments, 5 μM, 10 μM and 20 μM LFHP-1c increased the activity and migration number of model cells, reduced the number of apoptotic cells, ameliorated the excessive accumulation of intracellular reactive oxygen species, inhibited the over-activation of caspase-family and Bcl-2-family related proteins and mRNAs, and improved the mitochondrial dynamics of the fission and fusion states. Moreover, in vivo and in vitro experiments have shown that LFHP-1c can also upregulate the expression level of BDNF, inhibit the expression content of TNF-α and ROS, regulate the expression of proteins and mRNAs related to the RIPK1/RIPK3/MLKL pathway and mitochondrial dynamics, and reduce neuronal apoptosis.

Inhibition of PGAM5 expression level can reduce neuronal damage caused by chronic cerebral ischemia and hypoxia, which mainly prevents necroptosis by targeting the RIPK1/RIPK3/MLKL signaling pathway and regulates the downstream mitochondrial dynamics homeostasis system to prevent excessive mitochondrial fission, thus improving cognition and exerting cerebroprotective effects.

Mitochondria are of great importance in cell biology since they are major sites of adenosine triphosphate (ATP) production and are widely involved in different cellular pathways involved in the response to stress. During ATP production, reactive oxygen species (ROS) can be produced. While a small amount of ROS may be important for the regulation of physiological processes, at elevated levels they can turn into harmful agents leading to cellular damage. From a pathological perspective, it could be particularly interesting to focus on mitochondrial function in endothelial cells since they may be involved in the development of aging and in the onset of different diseases, including renal, cardio-metabolic, liver and neurodegenerative ones. However, to date, there are no surveys which address the above issues. To fill this gap, it may be valuable to collect recent findings about the role of mitochondria in the regulation of endothelial function, not only to increase knowledge about it but also for clinical applications. Here, we overview the most recent knowledge about the above issues in the view of characterizing the role of mitochondria in endothelial cells as an innovative potential target for the prevention of aging, as well as the treatment of the above pathological conditions.

Rapid activation of adenosine monophosphate-activated protein kinase (AMPK) induces phosphorylation of mitochondrial-associated proteins, a process by which phosphate groups are added to regulate mitochondrial function, thereby modulating mitochondrial energy metabolism, triggering an acute metabolic response, and sustaining metabolic adaptation through transcriptional regulation. AMPK directly phosphorylates folliculin interacting protein 1 (FNIP1), leading to the nuclear translocation of transcription factor EB (TFEB) in response to mitochondrial functions. While mitochondrial function is tightly linked to finely-tuned energy-sensing mobility, FNIP1 plays critical roles in glucose transport and sensing, mitochondrial autophagy, cellular stress response, and muscle fiber contraction. Consequently, FNIP1 emerges as a promising novel target for addressing aberrant mitochondrial energy metabolism. Recent evidence indicates that FNIP1 is implicated in mitochondrial biology through various pathways, including AMPK, mTOR, and ubiquitination, which regulate mitochondrial autophagy, oxidative stress responses, and skeletal muscle contraction. Nonetheless, there is a dearth of literature discussing the physiological mechanism of action of FNIP1 as a novel therapeutic target. This review outlines how FNIP1 regulates metabolic-related signaling pathways and enzyme activities, such as modulating mitochondrial energy metabolism, catalytic activity of metabolic enzymes, and the homeostasis of metabolic products, thereby controlling cellular function and fate in different contexts. Our focus will be on elucidating how these metabolite-mediated signaling pathways regulate physiological processes and inflammatory diseases.

Diabetic retinal neurodegeneration (DRN) is an early manifestation of diabetic retinopathy (DR) characterized by neurodegeneration that precedes microvascular abnormalities in the retina. DRN is characterized by apoptosis of retinal ganglion cells (involves alterations in retinal ganglion cells [RGCs], photoreceptors, amacrine cells and bipolar cells and so on), reactive gliosis, and reduced retinal neuronal function. Tau, a microtubule-associated protein, is a key mediator of neurotoxicity in neurodegenerative diseases, with functions in phosphorylation-dependent microtubule assembly and stabilization, axonal transport, and neurite outgrowth. The hyperphosphorylated tau (p-tau) loses its ability to bind to microtubules and aggregates to form paired helical filaments (PHFs), which further form neurofibrillary tangles (NFTs), leading to abnormal cell scaffolding and cell death. Studies have shown that p-tau can cause degeneration of RGCs in DR, making tau pathology a new pathophysiological model for DR. Here, we review the mechanisms by which p-tau contribute to DRN, including insulin resistance or lack of insulin, mitochondrial damage such as mitophagy impairment, mitochondrial axonal transport defects, mitochondrial bioenergetics dysfunction, and impaired mitochondrial dynamics, Abeta toxicity, and inflammation. Therefore, this article proposes that tau protein hyperphosphorylation plays a crucial role in the pathogenesis of DRN and may serve as a novel therapeutic target for combating DRN.

Mitochondrial diseases (MDs) are genetic disorders with diverse phenotypes that affect high-energy-demand organs, notably the central nervous system and muscles. Epilepsy is a common comorbidity, affecting 40%-60% of patients with MDs and significantly reducing their quality of life. This review discusses the different treatment modalities for epilepsy in patients with MDs. Advances in genetic sequencing have identified specific mutations in mitochondrial and nuclear DNA, enabling more precise diagnoses and tailored therapeutic strategies. Anti-seizure medications and dietary interventions, such as ketogenic diets and their variants, have been effective in reducing seizures and improving mitochondrial function. Emerging treatments include gene therapy, mitochondrial transplantation, and antioxidants such as EPI-743, which protect mitochondrial integrity and improve neurological function. Additionally, therapies that promote mitochondrial biogenesis, such as bezafibrate and epicatechin, are being explored for their potential to enhance mitochondrial proliferation and energy production. Gene therapy aims to correct genetic defects underlying MDs. Techniques like mitochondrial gene replacement and using viral vectors to deliver functional genes have shown promise in preclinical studies. Mitochondrial transplantation, an emerging experimental technique, involves transferring healthy mitochondria into cells with dysfunctional mitochondria. This technique has been demonstrated to restore mitochondrial function and energy metabolism in preclinical models. Patient-derived induced pluripotent stem cells can model specific mitochondrial dysfunctions in vitro, allowing for the testing of various treatments tailored to individual genetic and biochemical profiles. The future of mitochondrial medicine is promising, with the development of more targeted and personalized therapeutic strategies offering hope for improved management and prognosis of mitochondrial epilepsy.

Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive loss of neuronal structure and function. The pathogenesis is intricate and involves a network of interactions among multiple causes and systems. Mitochondria and Ca2+ signaling have long been considered to play important roles in the development of various NDs. Mitochondrial fission and fusion dynamics are important processes of mitochondrial quality control, ensuring the stability of mitochondrial structure and function. Mitochondrial fission and fusion imbalance and Ca2+ signaling disorders can aggravate the disease progression of NDs. In this review, we explore the relationship between mitochondrial dynamics and Ca2+ signaling in AD, PD, ALS, and HD, focusing on the roles of key regulatory proteins (Drp1, Fis1, Mfn1/2, and Opa1) and the association structures between mitochondria and the endoplasmic reticulum (MERCs/MAMs). We provide a detailed analysis of their involvement in the pathogenesis of these four NDs. By integrating these mechanisms, we aim to clarify their contributions to disease progression and offer insights into the development of therapeutic strategies that target mitochondrial dynamics and Ca2+ signaling. We also examine the progress in drug research targeting these pathways, highlighting their potential as therapeutic targets in the treatment of NDs.

Skin aging is the most prominent phenotype of host aging and is the consequence of a combination of genes and environment. Improving skin aging is essential for maintaining the healthy physiological function of the skin and the mental health of the human body. Mitochondria are vital organelles that play important roles in cellular mechanisms, including energy production and free radical balance. However, mitochondrial metabolism, mitochondrial dynamics, biogenesis, and degradation processes vary greatly in various cells in the skin. It is well known that mitochondrial dysfunction can promote the aging and its associated diseases of the skin, resulting in the damage of skin physiology and the occurrence of skin pathology. In this review, we summarize the important role of mitochondria in various skin cells, review the cellular responses to vital steps in mitochondrial quality regulation, mitochondrial dynamics, mitochondrial biogenesis, and mitochondrial phagocytosis, and describe their importance and specific pathways in skin aging.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are increasingly linked to mitochondrial dysfunction and neuroinflammation. Central to this link are mitochondrial damage-associated molecular patterns (mtDAMPs), including mitochondrial DNA, ATP, and reactive oxygen species, released during mitochondrial stress or damage. These mtDAMPs activate inflammatory pathways, such as the NLRP3 inflammasome and cGAS-STING, contributing to the progression of neurodegenerative diseases. This review delves into the mechanisms by which mtDAMPs drive neuroinflammation and discusses potential therapeutic strategies targeting these pathways to mitigate neurodegeneration. Additionally, it explores the cross-talk between mitochondria and the immune system, highlighting the complex interplay that exacerbates neuronal damage. Understanding the role of mtDAMPs could pave the way for novel treatments aimed at modulating neuroinflammation and slowing disease progression, ultimately improving patient outcome.

Ischaemia-reperfusion (IR) damage is an inevitable adverse effect of liver surgery. Recent research has found that IR damage is involved in severe mitochondrial dysfunction. Mitochondrial biosynthesis and dynamics control mitochondrial mass, distribution, and function. Sirtuin 3 (SIRT3) is widely known for preserving health and functionality of mitochondria. DEX has been proven to alleviate liver damage through antioxidant and anti-apoptotic pathways. But it's unclear how DEX protects mitochondria at this time. In this research, the mechanism behind the protective benefits of DEX was examined using the rat liver IR model and the rat liver cells (BRL-3 A) hypoxia reoxygenation (HR) model. We discovered that DEX treatment restored mitochondrial membrane potential, promoted ATP production, prevented oxidative stress, and decreased apoptosis in BRL-3 A cells. Furthermore, HR damage increased mitochondrial fission while decreasing mitochondrial fusion and biogenesis in BRL-3 A cells, which DEX partially corrected. The benefits of DEX on mitochondrial protection were reversed after addition of SR-18,292. Additionally, DEX showed the ability to enhance SIRT3 expression, and after cells were transfected with SIRT3 siRNA, DEX's effects on mitochondria were partially prevented. Similarly, in the rat model, DEX alleviating liver histopathological injury and oxidative stress. DEX inhibited IR-induced mitochondrial damage through improving ETC complex I- IV activities and ATP content, reducing apoptosis, controlling mitochondrial quality, and upregulating the expression of SIRT3. Additionally, our research shows that DEX's ability to protect the liver against IR damage is mediated by the modulation of mitochondrial quality control. Overall, the modification of SIRT3 activity could be responsible for this outcome.

Hepatocellular carcinoma (HCC) represents a significant global health challenge, characterized by a high incidence rate. Mitochondria have emerged as an important therapeutic target for HCC. Donafenib, a multi-receptor tyrosine kinase inhibitor, has been approved for the treatment of advanced HCC. However, the underlying mechanisms remain to be elucidated. In this study, we aim to investigate the effects of Donafenib on mitochondrial function in HCC cells. Firstly, we show that Donafenib induces mitochondrial oxidative stress in SNU-449 liver cancer cells by increasing mitochondrial ROS while reducing glutathione peroxidase (GPx) activity and the expression of Mn-SOD. We also demonstrate that Donafenib decreases mitochondrial membrane potential (MMP) and induces the opening of the mitochondrial permeability transition pore (mPTP). Furthermore, Donafenib reduces mitochondrial respiratory rate, COX IV activity, and ATP production. Notably, Donafenib induces mitochondrial fragmentation and reduces mitochondrial length by increasing the expression of DRP1, without affecting Mfn1 or Mfn2. Silencing of DRP1 protects against mitochondrial dysfunction induced by Donafenib, indicating that DRP1 plays a key role in mediating Donafenib's effects on mitochondrial function in HCC cells.

Mitochondria maintain bacterial traits because of their endosymbiotic origins, yet the host cell recognizes them as non-threatening since the organelles are compartmentalized. Nevertheless, the controlled release of mitochondrial components into the cytoplasm can initiate cell death, activate innate immunity, and provoke inflammation. This selective interruption of endosymbiosis as early as 2 billion years ago allowed mitochondria to become intracellular signaling hubs. Recent studies have found that the interruption of mitochondrial symbiosis may be closely related to the occurrence of various diseases, especially osteoporosis (OP). OP is a systemic bone disease characterized by reduced bone mass, impaired bone microstructure, elevated bone fragility, and susceptibility to fracture. The interruption of intra-mitochondrial symbiosis affects the energy metabolism of bone cells, leads to the imbalance of bone formation and bone absorption, and promotes the occurrence of osteoporosis. In this paper, we reviewed the mechanism of mitochondrial intersymbiosis interruption in OP, discussed the relationship between mitochondrial intersymbiosis interruption and bone marrow mesenchymal stem cells, osteoblasts and osteoclasts, as well as the inheritance and adaptation in the evolutionary process, and prospected the future research direction to provide new ideas for clinical treatment.

Alzheimer's disease (AD) stands out as the foremost prevalent neurodegenerative disorder, characterized by a complex etiology. Various mechanisms have been proposed to elucidate its onset, encompassing amyloid-beta (Aβ) toxicity, tau hyperphosphorylation, oxidative stress and reactive gliosis. The hallmark of AD comprises Aβ and tau aggregation. These misfolded protein aggregates trigger the activation of glial cells, primarily microglia. Microglial cells serve as a major source of inflammatory mediators and their cytotoxic activation has been implicated in various aspects of AD pathology. Activated microglia can adopt M1 or M2 phenotypes, where M1 promotes inflammation by increasing pro-inflammatory cytokines and M2 suppresses inflammation by boosting anti-inflammatory factors. Overexpressed pro-inflammatory cytokines include interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in adjacent brain regions. Furthermore, microglial signaling pathways dysregulated in AD are myeloid differentiation primary-response protein 88 (Myd 88), colony-stimulating factor-1 receptor (CSF1R) and dedicator of cytokinesis 2 (DOCK2), which alter the physiology. Despite numerous findings, the causative role of microglia-mediated neuroinflammation in AD remains elusive. This review concisely explores cellular and molecular mechanisms of activated microglia and their correlation with AD pathogenesis. Additionally, it highlights promising therapeutics targeting microglia modulation, currently undergoing preclinical and clinical studies, for developing effective treatment for AD.

The association between per- and polyfluoroalkyl substances (PFAS) and mitochondrial DNA copy number (mtDNAcn) in children, and the potential impact of estimated glomerular filtration rate (eGFR) on this association, remains unclear.

We conducted a panel study with up to 3 surveys over 3 seasons in Weinan and Guangzhou, China. A total of 284 children aged 4-12 years were available, with 742 measurements of 11 PFAS and mtDNAcn. Linear mixed-effect (LME), quantile g-computation (qgcomp), weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models were used to investigate the associations of individuals and a mixture of PFAS with mtDNAcn, and the modifying effect of eGFR on these associations.

Legacy PFAS, including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorooctane sulfonate (PFOS) and emerging PFAS, 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), were significantly associated with decreased mtDNAcn in a linear dose-response manner (FDR <0.05). The multiple PFAS model showed each doubling increase in PFOA related to a 6.36% (95%CI: -10.22%, -2.34%) decrement in mtDNAcn. Meanwhile, the PFAS mixture was dose-responsive related to decreased mtDNAcn, with PFOA being the largest contributor, followed by PFUnDA and PFNA. Notably, eGFR modified the inverse association between PFOA and mtDNAcn (P-int = 0.039), with a more pronounced decrement in children with an eGFR below the 20th value (101.71 mL/min/1.73m2). In addition, age significantly modified the relationship between PFOA and decreased mtDNAcn (P-int = 0.028), with a stronger association in those aged 7 years or older.

Both individual and the mixture of legacy and emerging PFAS exposure were associated with decreased mtDNAcn in children, with PFOA as the main contributor and modification of eGFR.

Vascular endothelial cells form a single layer of flat cells that line the inner surface of blood vessels, extending from large vessels to the microvasculature of various organs. These cells are crucial metabolic and endocrine components of the body, playing vital roles in maintaining circulatory stability, regulating vascular tone, and preventing coagulation and thrombosis. Endothelial cell injury is regarded as a pivotal initiating factor in the pathogenesis of various diseases, triggered by multiple factors, including infection, inflammation, and hemodynamic changes, which significantly compromise vascular integrity and function. This review examines the causes, underlying molecular mechanisms, and potential therapeutic approaches for endothelial cell injury, focusing specifically on endothelial damage in cardiac ischemia/reperfusion (I/R) injury, sepsis, and diabetes. It delves into the intricate signaling pathways involved in endothelial cell injury, emphasizing the roles of oxidative stress, mitochondrial dysfunction, inflammatory mediators, and barrier damage. Current treatment strategies-ranging from pharmacological interventions to regenerative approaches and lifestyle modifications-face ongoing challenges and limitations. Overall, this review highlights the importance of understanding endothelial cell injury within the context of various diseases and the necessity for innovative therapeutic methods to improve patient outcomes.

Studies using the embryos of the freshwater prawn Macrobrachium olfersii have reported changes in embryonic cells after exposure to ultraviolet B (UVB) radiation, such as DNA damage and apoptosis activation. Considering the importance of mitochondria in embryonic cells, this study aimed to characterize the aspects of mitochondrial morphofunctionality in M. olfersii embryos and mitochondrial responses to UVB radiation exposure. The coding sequences of genes Tfam, Nrf1, Mfn1, and Drp1 were identified from the transcriptome of M. olfersii embryos. The phylogenetic relationship showed strong amino acid identity and a highly conserved nature of the sequences. Additionally, the number of mitochondrial DNA (mtDNA) copies were higher in the early embryonic days. The results showed that the expression of the analyzed genes was highly regulated during embryonic development, increasing their levels near hatching. Furthermore, when embryos were exposed to UVB radiation, mitochondrial biogenesis was activated, recognized by higher levels of transcripts of genes Tfam and Nrf1, accompanied by mitochondrial fission. Additionally, these mitochondrial events were supported by an increase of mtDNA copies. Our results showed that UVB radiation was able to change the mitochondrial morphofunctionality, and under the current knowledge, certainly compromise embryonic cellular integrity. Additionally, mitochondria is an important cellular target of this radiation and its responses can be used to assess environmental stress caused by UVB radiation in embryos of aquatic species.

Brain-derived neurotrophic factor (BDNF) plays a pivotal role in neuronal development, synaptic plasticity, and overall neuronal health by binding to its receptor, tyrosine receptor kinase B (TrkB). This review delves into the intricate mechanisms through which BDNF-TrkB signaling influences mitochondrial function and potentially influences pathology in neurodegenerative diseases. This review highlights the BDNF-TrkB signaling pathway which regulates mitochondrial bioenergetics, biogenesis, and dynamics, mitochondrial processes vital for synaptic transmission and plasticity. Furthermore, we explore how the BDNF-TrkB-PKA signaling in the cytosol and in mitochondria affects mitochondrial transport and distribution and mitochondrial content, which is crucial for supporting the energy demands of synapses. The dysregulation of this signaling pathway is linked to various neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by mitochondrial dysfunction and reduced BDNF expression. By examining seminal studies that have characterized this signaling pathway in health and disease, the present review underscores the potential of enhancing BDNF-TrkB signaling to mitigate mitochondrial dysfunction in neurodegenerative diseases, offering insights into therapeutic strategies to enhance neuronal resilience and function.

Neuropathic pain poses a significant clinical challenge, largely due to the incomplete understanding of its molecular mechanisms, particularly the role of mitochondrial dysfunction. Bioinformatics analysis revealed that pyroptosis and inflammatory responses induced by spared nerve injury (SNI) in the spinal dorsal horn play a critical role in the initiation and persistence of neuropathic pain. Among the factors involved, TSPO (translocator protein) emerged as a key regulator. Our experimental findings showed that TSPO expression was upregulated during neuropathic pain, accompanied by mitochondrial dysfunction, specifically manifested as impaired mitochondrial biogenesis, disrupted mitochondrial dynamics (including insufficient expression of mitochondrial biogenesis and fusion-related proteins, as well as significantly increased expression of fission-related proteins), and activation of pyroptosis. Pharmacological upregulation of TSPO, but not its downregulation, effectively alleviated SNI-induced pain hypersensitivity, improving mitochondrial function and reducing pyroptosis. Immunofluorescence staining confirmed that TSPO was primarily localized in astrocytes, and its expression mirrored the protective effects on mitochondrial health and pyroptosis prevention. PCR array analysis suggested a strong association between TSPO and the mitochondrial regulation pathway AMPK-PGC-1α. Notably, inhibition of AMPK-PGC-1α abolished TSPO effects on mitochondrial balance and pyroptosis suppression. Furthermore, Mendelian randomization analysis of GWAS data indicated that increased TSPO expression was linked to pain relief. Through drug screening, molecular docking, and behavioral assays, we identified zopiclone as a promising TSPO-targeting drug for pain treatment. In summary, this study enhances our understanding of the molecular interplay between TSPO, mitochondrial health, and neuropathic pain, highlighting TSPO as a potential therapeutic target for pain management.

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease. Licorice and dried ginger decoction (LGD) is traditional Chinese medicine prescription with multiple effects. Glycyrrhetinic acid (GA) is the main bioactive components of LGD, which has been proven to have a relieving effect on various inflammatory diseases. Siglec-1 is a cell surface sialoadhesin and has been confirmed to be overexpressed in COPD and facilitate inflammatory reaction. This study is aimed to probe the interaction between LGD, GA, and siglec-1.

Cigarette smoke (CS) combined with lipopolysaccharide (LPS) treatment was utilized to construct a COPD rat model. Cigarette smoke extract (CSE) was utilized to induce alveolar macrophage NR8383 to construct a COPD cell model. HE staining was applied for measuring histopathological changes of COPD rats. Enzyme-linked immunosorbent assay (ELISA), reverse transcription real-time polymerase chain reaction (RT-qPCR), and western blot were applied for testing the concentrations and expressions of proinflammatory factors. High performance liquid chromatography-tandem mass spectrometry (HPLC-MS) analysis was utilized to determine the combination between siglec-1 and GA. JC-1 assay was utilized to evaluate mitochondrial function. Reactive oxygen species (ROS) production was tested by dichloro-dihydro-fluorescein diacetate (DCFH-DA) staining.

LGD treatment notably alleviated lung injury and inflammatory response in COPD rats. In CSE-induced cells, LGD treatment suppressed the contents of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8. Sialic-acid-binding Ig-like lectin 1 (Siglec-1) expression induced by CS was decreased after LGD treatment. Furthermore, we proved that GA could target siglec-1 to regulate the inflammatory response in COPD rats and cells. Additionally, GA could reduce ROS production and alleviate mitochondrial dysfunction to suppress COPD progression.

LGD inhibits inflammation and alleviates mitochondrial dysfunction in COPD by targeting siglec-1.

Aberrations emerging in mitochondrial homeostasis are restrained by mitophagy to control mitochondrial integrity, bioenergetics signaling, metabolism, oxidative stress, and apoptosis. The mitophagy-accompanied mitochondrial processes that occur in a dysregulated condition act as drivers for cancer occurrence. In addition, the enigmatic nature of mitophagy in cancer cells modulates the cellular proteome, creating challenges for therapeutic interventions. Several reports found the role of cellular signaling pathways in cancer to modulate mitophagy to mitigate stress, immune checkpoints, energy demand, and cell death. Thus, targeting mitophagy to hinder oncogenic intracellular signaling by promoting apoptosis, in hindsight, might have an edge against cancer. This review highlights the receptors and adaptors, and the involvement of many proteins in mitophagy and their role in oncogenesis. It also provides insight into using mitophagy as a potential target for therapeutic intervention in various cancer types.

Intracerebral hemorrhage (ICH) is a major global health issue with high mortality and disability rates. Following ICH, the hematoma exerts direct pressure on brain tissue, and blood entering the brain directly damages neurons and the blood-brain barrier. Subsequently, oxidative stress, inflammatory responses, apoptosis, brain edema, excitotoxicity, iron toxicity, and metabolic dysfunction around the hematoma further exacerbate brain tissue damage, leading to secondary brain injury (SBI). Mitochondria, essential for energy production and the regulation of oxidative stress, are damaged after ICH, resulting in impaired ATP production, excessive reactive oxygen species (ROS) generation, and disrupted calcium homeostasis, all of which contribute to SBI. Therefore, a central factor in SBI is mitochondrial dysfunction. Mitochondrial dynamics regulate the shape, size, distribution, and quantity of mitochondria through fusion and fission, both of which are crucial for maintaining their function. Fusion repairs damaged mitochondria and preserves their health, while fission helps mitochondria adapt to cellular stress and removes damaged mitochondria through mitophagy. When this balance is disrupted following ICH, mitochondrial dysfunction worsens, oxidative stress and metabolic failure are exacerbated, ultimately contributing to SBI. Targeting mitochondrial dynamics offers a promising therapeutic approach to restoring mitochondrial function, reducing cellular damage, and improving recovery. This review explores the latest research on modulating mitochondrial dynamics and highlights its potential to enhance outcomes in ICH patients.

Mitochondrial homeostasis is crucial for maintaining cellular energy production and preventing oxidative stress, which is essential for overall cellular function and longevity. Mitochondrial damage and dysfunction often occur concomitantly in myocardial ischemia-reperfusion injury (MIRI). Notoginsenoside R1 (NGR1), a unique saponin from the traditional Chinese medicine Panax notoginseng, has been shown to alleviate MIRI in previous studies, though its precise mechanism remains unclear. This study aimed to elucidate the mechanisms of NGR1 in maintaining mitochondrial homeostasis in hypoxia/reoxygenation (H/R) H9c2 cells. The results showed that NGR1 pretreatment effectively increased cell survival rates post-H/R, reduced lactate dehydrogenase (LDH) leakage, and mitigated cell damage. Further investigation into mitochondria revealed that NGR1 alleviated mitochondrial structural damage, improved mitochondrial membrane permeability transition pore (mPTP) persistence, and prevented mitochondrial membrane potential (Δψm) depolarization. Additionally, NGR1 pretreatment enhanced ATP levels, increased the activity of mitochondrial respiratory chain complexes I-V after H/R, and reduced excessive mitochondrial reactive oxygen species (mitoROS) production, thereby protecting mitochondrial function. Further analysis indicated that NGR1 upregulated the expression of mitochondrial biogenesis-related proteins (PGC-1α, Nrf1, Nrf2) and mitochondrial fusion proteins (Opa1, Mfn1, Mfn2), while downregulating mitochondrial fission proteins (Fis1, Drp1) and reducing mitochondrial autophagy (mitophagy) levels, as well as the expression of mitophagy-related proteins (Pink1, Parkin, BNIP3) post-H/R. Therefore, this study showed that NGR1 can maintain mitochondrial homeostasis by regulating mitophagy, mitochondrial fission-fusion dynamics, and mitochondrial biogenesis, thereby alleviating H9c2 cell H/R injury and protecting cardiomyocytes.

The adverse impact of disturbmitochondrialbiogenesis onearly brain injury (EBI) following subarachnoid haemorrhage (SAH) has been broadly recognized and is closely associated with oxidative stress and neuronal apoptosis. Previous studies have indicated the therapeutic potential of Ropinirole, a dopamine D2 agonist, in Ischemic Stroke. However, there is a lack of evidence regarding the ability of Ropinirole to enhance mitochondrial biogenesis and quality control after subarachnoid haemorrhage. The objective of this study is to investigate the effects of Ropinirole specific doses (10 & 20 mg/kg b. wt.) on mitochondria dysfunction in endovascular perforation SAH model in male Wistar rat. An endovascular perforation model was established using male Wistar rats that had sustained SAH injury. After the SAH injury, SAH grading on blood clot, Nissl staining, and neurobehavioral assessment were used to determine the severity. ROS and MMP, which are indicators of oxidative stress, were examined using flow cytometry. The findings demonstrated that the use of Ropinirole improved neurobehavioral outcomes, decreased brain edema, and reduced oxidative stress and mitochondrial based apoptosis. Further research showed that, Ropinirole therapy inhibit Drp1-mediated fission by accelerating the activity of fusion protein Mfn2/OPA1 along with regulating the translocation of PGC1-α and SIRT3 through restricting cytochrome C inside mitochondria to maintain mitochondrial metabolism. Ropinirole exerted neuroprotective effects by improving mitochondrial activity in a PGC1-α/SIRT3-dependent way via regulating Drp1 mediated fission. The effective treatment for SAH-induced EBI may involve increasing biogenesis and inhibiting excessive mitochondrial fission with Ropinirole.

Mitochondrial dysfunction is one of the leading causes of disease development. Dysfunctional mitochondria limit energy production, increase reactive oxygen species generation, and trigger apoptotic signals. Photobiomodulation is a noninvasive, nonthermal technique involving the application of monochromatic light with low energy density, inducing non-thermal photochemical effects at the cellular level, and it has been used due to its therapeutic potential. This review focuses on the mitochondrial dynamic's role in various diseases, evaluating the possible therapeutic role of low-power lasers (LPL) and light-emitting diodes (LED). Studies increasingly support that mitochondrial dysfunction is correlated with severe neurodegenerative diseases such as Parkinson's, Huntington's, Alzheimer's, and Charcot-Marie-Tooth diseases. Furthermore, a disturbance in mitofusin activity is also associated with metabolic disorders, including obesity and type 2 diabetes. The effects of PBM on mitochondrial dynamics have been observed in cells using a human fibroblast cell line and in vivo models of brain injury, diabetes, spinal cord injury, Alzheimer's disease, and skin injury. Thus, new therapies aiming to improve mitochondrial dynamics are clinically relevant. Several studies have demonstrated that LPL and LED can be important therapies to improve health conditions when there is dysfunction in mitochondrial dynamics.

Understanding the spatiotemporal organization of components within living systems requires the highest resolution possible. Microscopy approaches that allow for a resolution below 250 nm include electron and super-resolution microscopy (SRM). The latter combines advanced imaging techniques and the optimization of image processing methods. Over the last two decades, various SRM-related approaches have been introduced, especially those relying on single molecule localization microscopy (SMLM). To develop and apply SMLM approaches, mitochondria are an ideal cellular compartment due to their size, which is below the standard diffraction limit. Furthermore, mitochondria are a dynamic yet narrow compartment, and a resolution below 250 nm is required to study their composition and multifaceted functions. To this end, several SMLM technologies have been used to reveal mitochondrial composition. However, there is still room for improvement in existing techniques to study protein-protein interactions and protein dynamics within this compartment. This review aims to offer an updated overview of the existing SMLM techniques and probes associated with mitochondria to enhance their resolution at the nanoscale. Last, it paves the way for future SMLM improvements to better resolve mitochondrial dynamics and functions.

Polyvinyl chloride microplastics (PVC-MPs) and Cadmium (Cd) are widely occurring water pollutants that interact with each other to exert toxic effects. As a waterfowl, Muscovy duck is more susceptible to PVC-MPs and Cd than land poultry. In this study, Muscovy duck was used as a research model, and 10 mg/L PVC-MPs and 50 mg/kg Cd were used alone and in combine to explore the effect on the kidney of Muscovy duck. We found that treatment of Cd or PVC-MPs alone changed the kidney weight, increased creatinine and urea nitrogen content, and disrupted oxidative balance and macro/trace element metabolism, while the combination of PVC-MPs+Cd reduced the accumulation of Cd in the kidney. In addition, treatment of Cd and PVC-MPs alone caused mitochondrial damage, increase or decrease of mitochondria-associated proteins (Fis1, Drp1, PGC-1α, Nrf1), and Nrf2 signaling pathway plays a key role in detoxification and alleviation of oxidative stress, and we found that PVC-MPs+Cd treatment recovered related proteins (Nrf2, Keap-1, HO-1, NQO1, AC-SOD2, SOD2) compared with the Cd and PVC-MPs alone treatment. Finally, we detected changes in apoptosis-related proteins and genes (Caspase-3, Caspase-9, Bax, Bcl-2, Cytc) and TUNEL staining, and after PVC-MPs+Cd treatment, apoptosis-related proteins/genes recovered and the apoptosis rate decreased compared with the Cd and PVC-MPs alone treatment. These results indicate that renal function is impaired, oxidative stress and trace element metabolism disorder, nuclear factor-E2 related factor 2 (Nrf2) is activated into the nucleus to induce the expression of related antioxidant proteins (such as HO-1, NQO1). These injuries can induce mitochondrial damage and eventually lead to renal cell apoptosis. To sum up, these evidence show that Cd or PVC-MPs can induce kidney oxidative damage, trace element metabolism disorder, mitochondrial damage and apoptosis.

The highly reactive hypobromous acid (HOBr), which is generated after chlorination process of tap water, acts as a precursor of toxic brominated disinfection by-products (Br-DBPs) and further reacts with organic matter. In addition, HOBr produced from the oxidation of Br- during the degradation of pollutants by peroxymonosulfate (PMS, HSO5-) can be considered as the cause of the expedited degradation of pollutants. Therefore, it is particularly important to detect HOBr level in the water environment. Resazurin was selected as a fluorescent probe for selective recognition of HOBr in the water environment. The probe exhibited excellent spectral performance and showed high sensitivity to HOBr (LOD = 515 nM). This method has a relatively ideal recovery rate for HOBr detection in environmental water samples. Furthermore, the HOBr production during the chlorination disinfection process was simulated and the HOBr generated from this process was detected by the probe. Importantly, the process of HOBr recognition by the probe is accompanied by the change of color. Based on this, the relationship between the change of color B/G value and HOBr concentration was successfully constructed. The probe was loaded on the filter paper to make a test strip, which was utilized to the detection of HOBr. Collectively, this work provided a promising and powerful method for HOBr detection in the environment.

With the increasing prevalence of hypertension, the incidence of kidney diseases is also increasing, resulting in a serious public burden. Jiangya Tongluo decoction (JYTL), a recognized prescription in traditional Chinese medicine (TCM), is commonly used to calm an overactive liver and reduce excess yang, while also promoting blood flow to alleviate obstructions in the meridians. Previous research has indicated that JYTL may help mitigate kidney damage caused by hypertension; however, the underlying mechanisms have not been thoroughly assessed.

First, an amalgamation of UPLC-QE/MS and network pharmacology techniques was employed to pinpoint potential active components, primary targets, and crucial action mechanisms of JYTL in treating hypertensive nephropathy (HN). Then, we used spontaneous hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) to evaluate the efficacy of JYTL on HN with valsartan as a positive reference. We also conducted DCFH-DA fluorescence staining in rat renal tissues to detect the level of ROS. Western blotting and immunohistochemistry were performed to investigate further the effect of JYTL decoction on key targets and signaling pathways.

Through UPLC-QE/MS and network analysis, 189 active ingredients and 5 hub targets were identified from JYTL. GSEA in the MitoCarta3.0 database and PPI network analysis revealed that JYTL predominantly engages in the Sirt1-mitophagy signaling pathway. Tanshinone iia, quercetin, and adenosine in JYTL are the main active ingredients for treating HN. In vivo validation showed that JYTL decoction could improve kidney function, ameliorate tubulointerstitial fibrosis (TIF), and improve mitochondrial function by inhibiting ROS production and regulating mitochondrial dynamics in SHRs. JYTL treatment could also increase the expression of SIRT1, PGC-1α, Nrf1, and TFAM, and activate PINK1/Parkin-mediated mitophagy.

JYTL decoction may exert renal function protective and anti-fibrosis effects in HN by ameliorating mitochondrial function and regulating the SIRT1/PGC-1α-mitophagy pathway.

This review consolidates a decade of research on fumarylacetoacetate hydrolase domain containing protein 1 (FAHD1), a mitochondrial oxaloacetate tautomerase and decarboxylase with profound implications in cellular metabolism. Despite its critical role as a regulator in mitochondrial metabolism, FAHD1 has remained an often-overlooked enzyme in broader discussions of mitochondrial function. After more than 12 years of research, it is increasingly clear that FAHD1's contributions to cellular metabolism, oxidative stress regulation, and disease processes such as cancer and aging warrant recognition in both textbooks and comprehensive reviews. The review delves into the broader implications of FAHD1 in mitochondrial function, emphasizing its roles in mitigating reactive oxygen species (ROS) levels and regulating complex II activity, particularly in cancer cells. This enzyme's significance is further highlighted in the context of aging, where FAHD1's activity has been shown to influence cellular senescence, mitochondrial quality control, and the aging process. Moreover, FAHD1's involvement in glutamine metabolism and its impact on cancer cell proliferation, particularly in aggressive breast cancer subtypes, underscores its potential as a therapeutic target. In addition to providing a comprehensive account of FAHD1's biochemical properties and structural insights, the review integrates emerging hypotheses regarding its role in metabolic reprogramming, immune regulation, and mitochondrial dynamics. By establishing a detailed understanding of FAHD1's physiological roles and therapeutic potential, this work advocates for FAHD1's recognition in foundational texts and resources, marking a pivotal step in its integration into mainstream metabolic research and clinical applications in treating metabolic disorders, cancer, and age-related diseases.

Copper (Cu) is essential for brain development and function, yet its overload induces neuronal damage and contributes to neurodegeneration and other neurological disorders. Multiple studies demonstrated that Cu neurotoxicity is associated with mitochondrial dysfunction, routinely assessed by reduction of mitochondrial membrane potential. Nonetheless, the role of alterations of mitochondrial dynamics in brain mitochondrial dysfunction induced by Cu exposure is still debatable. Therefore, the objective of the present narrative review was to discuss the role of mitochondrial dysfunction in Cu-induced neurotoxicity with special emphasis on its influence on brain mitochondrial fusion and fission, as well as mitochondrial clearance by mitophagy. Existing data demonstrate that, in addition to mitochondrial electron transport chain inhibition, membrane damage, and mitochondrial reactive oxygen species (ROS) overproduction, Cu overexposure inhibits mitochondrial fusion by down-regulation of Opa1, Mfn1, and Mfn2 expression, while promoting mitochondrial fission through up-regulation of Drp1. It has been also demonstrated that Cu exposure induces PINK1/Parkin-dependent mitophagy in brain cells, that is considered a compensatory response to Cu-induced mitochondrial dysfunction. However, long-term high-dose Cu exposure impairs mitophagy, resulting in accumulation of dysfunctional mitochondria. Cu-induced inhibition of mitochondrial biogenesis due to down-regulation of PGC-1α further aggravates mitochondrial dysfunction in brain. Studies from non-brain cells corroborate these findings, also offering additional evidence that dysregulation of mitochondrial dynamics and mitophagy may be involved in Cu-induced damage in brain. Finally, Cu exposure induces cuproptosis in brain cells due mitochondrial proteotoxic stress, that may also contribute to neuronal damage and pathogenesis of certain brain diseases. Based on these findings, it is assumed that development of mitoprotective agents, specifically targeting mechanisms of mitochondrial quality control, would be useful for prevention of neurotoxic effects of Cu overload.

The mitochondrion, one of the important cellular organelles, has the major function of generating adenosine triphosphate and plays an important role in maintaining cellular homeostasis, governing signal transduction, regulating membrane potential, controlling programmed cell death and modulating cell proliferation. The dynamic balance of mitochondrial volume is an important factor required for maintaining the structural integrity of the organelle and exerting corresponding functions. Changes in the mitochondrial volume are closely reflected in a series of biological functions and pathological changes. The mitochondrial volume is controlled by the osmotic balance between the cytoplasm and the mitochondrial matrix. Thus, any disruption in the influx of the main ion, potassium, into the cells can disturb the osmotic balance between the cytoplasm and the matrix, leading to water movement between these compartments and subsequent alterations in mitochondrial volume. Recent studies have shown that mitochondrial volume homeostasis is closely implicated in a variety of diseases. In this review, we provide an overview of the main influencing factors and research progress in the field of mitochondrial volume homeostasis.

Activation of sympathetic tone is important for cartilage degradation in osteoarthritis (OA). Recent studies reported that sympathetic signals can affect the mitochondrial function of target cells. It is unknown whether this effect exits in chondrocytes and affects chondrocyte catabolism. The contribution of mitochondrial dynamics in the activation of α2-adrenergic signal-mediated chondrocyte catabolism was investigated in this study.

Primary chondrocytes were stimulated with norepinephrine (NE) alone, or pretreated with an α2-adrenergic receptor (Adra2) antagonist (yohimbine) and followed by stimulation with NE. Changes in chondrocyte metabolism and their mitochondrial dynamics were investigated.

We demonstrated that NE stimulation induced increased gene and protein expressions of matrix metalloproteinase-3 and decreased level of aggrecan by chondrocytes. This was accompanied by upregulated mitochondriogenesis and the number of mitochondria, when compared with the vehicle-treated controls. Mitochondrial fusion and fission, and mitophagy also increased significantly in response to NE stimulation. Inhibition of Adra2 attenuated chondrocyte catabolism and mitochondrial dynamics induced by NE.

The present findings indicate that upregulation of mitochondrial dynamics through mitochondriogenesis, fusion, fission, and mitophagy is responsible for activation of α2-adrenergic signal-mediated chondrocyte catabolism. The hypothesis that "α2-adrenergic signal activation promotes cartilage degeneration in temporomandibular joint osteoarthritis (TMJ-OA) by upregulating mitochondrial dynamics in chondrocytes" is validated. This represents a new regulatory mechanism in the chondrocytes of TMJ-OA that inhibits abnormal activation of mitochondrial fusion and fission is a potential regulator for improving mitochondrial function and inhibiting chondrocyte injury and contrives a potentially innovative therapeutic direction for the prevention of TMJ-OA.