Role Of Mitochondrial Dysfunction Research Articles

Increased TSPO alleviates neuropathic pain by preventing pyroptosis via the AMPK-PGC-1α pathway

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.Graphical

The role of mitochondrial dysfunction in the cytotoxic synergistic effect of gemcitabine and arsenic on breast cancer.

Breast cancer is the most common type of cancer in women worldwide. A common approach to cancer treatment in clinical practice is to use a combination of drugs to enhance the anticancer activity of drugs while reducing their side effects. In this regard, we evaluated the effectiveness of combined treatment with gemcitabine (GCB) and arsenic (ATO) and how they affect the cell death pathway in cancer cells. Cytotoxic activity of drugs individually or combined against MDA-MB-231 and MCF-7 was performed by MTT method and isobolographic analysis was used to determine the interaction between these factors. The combination of ATO and GCB showed synergistic anti-cancer activity (CI < 1) in both cancer cell lines. The combination of ATO and GCB induced sub-G1 phase arrest, apoptosis and death rates in MCF-7 and MDA-MB-231 cells. The apoptotic response induced by the combination of GCB and ATO was dependent on caspase 3/7. Combined treatment with mitochondrial membrane potential (MMP) reduction and increased reactive oxygen species (ROS) production caused mitochondrial dysfunction. Co-treatment significantly reduced catalase (CAT) activity in both cancer cells compared to the control group and cells treated with each monotherapy. A significant decrease in cellular GSH was observed in cancer cells treated with ATO and GCB. In addition, migration and invasion were significantly reduced in breast cancer cells treated with the combination of ATO and GCB compared to cells treated with ATO and GCB. In conclusion, the combined treatment of ATO and GCB synergistically increased the anti-cancer activity, and these findings provide an effective approach for the treatment of breast cancer. To the best of our knowledge, this is the first study showing promising results for combination therapy with ATO and GCB in breast cancer.

Platelet Mitochondrial Function and Endogenous Coenzyme Q10 Levels Could Be Used as Markers of Mitochondrial Health in Infertile Men: A Pilot Study.

Fertility disorders are a worldwide problem affecting 8-12% of the population, with the male factor substantially contributing to about 40-50% of all infertility cases. Mitochondria, crucial organelles for cellular viability, play a pivotal role in the processes of spermatogenesis and significantly affect sperm quality and their fertilizing ability. Mitochondrial oxidative phosphorylation (OXPHOS) dysfunction, reduced energy supply for sperm, reduced endogenous coenzyme Q10 (CoQ10) levels, and oxidative stress are among the main factors that contribute to male infertility. There is great interest in the role of mitochondrial dysfunction in male infertility, and the diagnosis and assessment of mitochondrial health in infertile men present challenges. Platelets are a source of viable mitochondria that can be obtained non-invasively. Changes in platelet mitochondrial respiration were documented in various diseases, confirming platelet mitochondrial bioenergetics as a marker of systemic mitochondrial health. The aim of our study was to determine whether (a) platelet mitochondrial bioenergetics and CoQ10 levels could be used as metabolic markers of mitochondrial health in infertile men and whether (b) the parameters of mitochondrial respiration in platelets correlate with sperm parameters. The high-resolution respirometry method was used for platelet bioenergetics, and the high-performance liquid chromatography (HPLC) method was used for CoQ10 level measurement. The static oxidation-reduction potential (sORP) of the ejaculate was evaluated by MiOXSYS®System. We found a deficit in mitochondrial complex I-linked OXPHOS and electron transfer capacity and CoQ10 and α-tocopherol levels in infertile men. The proportion of sperm, heads, and midpiece abnormalities correlated negatively with the complex I-linked parameters of platelet mitochondrial bioenergetics. We suppose that dysfunctional mitochondria contribute to increased oxidative stress, and these imbalances can be considered a cause of Male Oxidative Stress Infertility (MOSI). Our results suggest that platelet mitochondrial function and the endogenous levels of CoQ10 in platelets could be used as metabolic markers for monitoring mitochondrial health and targeted therapy in infertile men. sORP could be a useful clinical biomarker of MOSI.

Impact of ageing and disuse on neuromuscular junction and mitochondrial function and morphology: Current evidence and controversies.

Inactivity and ageing can have a detrimental impact on skeletal muscle and the neuromuscular junction (NMJ). Decreased physical activity results in muscle atrophy, impaired mitochondrial function, and NMJ instability. Ageing is associated with a progressive decrease in muscle mass, deterioration of mitochondrial function in the motor axon terminals and in myofibres, NMJ instability and loss of motor units. Focusing on the impact of inactivity and ageing, this review examines the consequences on NMJ stability and the role of mitochondrial dysfunction, delving into their complex relationship with ageing and disuse. Evidence suggests that mitochondrial dysfunction can be a pathogenic driver for NMJ alterations, with studies revealing the role of mitochondrial defects in motor neuron degeneration and NMJ instability. Two perspectives behind NMJ instability are discussed: one is that mitochondrial dysfunction in skeletal muscle triggers NMJ deterioration, the other envisages dysfunction of motor terminal mitochondria as a primary contributor to NMJ instability. While evidence from these studies supports both perspectives on the relationship between NMJ dysfunction and mitochondrial impairment, gaps persist in the understanding of how mitochondrial dysfunction can cause NMJ deterioration. Further research, both in humans and in animal models, is essential for unravelling the mechanisms and potential interventions for age- and inactivity-related neuromuscular and mitochondrial alterations.

Mitochondrial Dysfunction in Atrial Fibrillation: The Need for a Strong Pharmacological Approach

Despite great progress in treating atrial fibrillation (AF), especially with the development of increasingly effective invasive techniques for AF ablation, many unanswered questions remain regarding the pathogenic mechanism of the arrhythmia and its prevention methods. The development of AF is based on anatomical and functional alterations in the cardiomyocyte resulting from altered ionic fluxes and cardiomyocyte electrophysiology. Electric instability and electrical remodeling underlying the arrhythmia may result from oxidative stress, also caused by possible mitochondrial dysfunction. The role of mitochondrial dysfunction in the pathogenesis of AF is not yet fully elucidated; however, the reduction in AF burden after therapeutic interventions that improve mitochondrial fitness tends to support this concept. This selected review aims to summarize the mechanisms of mitochondrial dysfunction related to AF and the current pharmacological treatment options that target mitochondria to prevent or improve the outcome of AF.

Ana Cristina Andreazza: Driven by curiosity – transforming mental health through mitochondrial innovation

Dr. Ana Cristina Andreazza is a Professor of Pharmacology Toxicology and Psychiatry at the University of Toronto, holding the Thomas C. Zachos Chair in Mitochondrial Research and a Tier II Canada Research Chair in Molecular Pharmacology of Mood Disorders. As the visionary Founder and Scientific Director of the Mitochondrial Innovation Initiative (Mito2i), she leads pioneering research on the role of mitochondrial dysfunction in neurological and psychiatric diseases, organ transplants, and novel therapeutic strategies. Her groundbreaking work has revolutionized our understanding of the relationship between mitochondrial function and mental health disorders, particularly bipolar disorder. Dr. Andreazza's career was inspired by early curiosity, family influence, and a commitment to reduce the stigma surrounding metabolic and psychiatric conditions. Her innovative work bridges multiple disciplines, aiming to discover biomarkers that could enable personalized treatments in mental health. A recipient of numerous prestigious awards, including membership in the Royal Society of Canada College of New Scholars, Dr. Andreazza has published over 200 peer-reviewed papers and is internationally recognized for her contributions to metabolic psychiatry. In this Genomic Press Interview, she shares insights into her remarkable journey from studying wine chemistry in Brazil to becoming a leading force in mitochondrial research while discussing her perspectives on collaborative science and innovation. Driven by a passion for teaching and collaborative science, Dr. Andreazza continues to foster innovation and mentorship in the mitochondrial research community.

Mitochondrial dysfunction in myasthenia gravis: Exploring directions for future immunotherapy? A review.

Myasthenia gravis (MG) is an acquired autoimmune disease characterized by impaired transmission at the neuromuscular junction, primarily manifesting as fluctuating muscle weakness, fatigability, and partial paralysis. Due to its long disease course, treatment resistance, and frequent relapses, it places a significant burden on patients and their families. In recent years, advances in molecular biology have provided growing evidence that mitochondrial dysfunction impairs muscle function and affects immune cell proliferation and differentiation in patients. Mitochondria, as the cell's energy source, play a critical role in various pathological processes in MG, including oxidative stress, dynamic abnormalities, mitophagy, and mitochondrial metabolism. The role of mitochondrial dysfunction in the pathogenesis of MG has garnered increasing attention. This manuscript primarily explores mitochondrial function and abnormal morphological changes in MG, as well as mitochondrial quality control, metabolic reprogramming, and their potential mechanisms in the pathological changes of the disease. It also reviews the current status of drug therapies aimed at improving mitochondrial function. The goal is to provide novel perspectives and strategies for future mitochondrial-targeted therapies in MG.

Mitochondria as a primary determinant of angiogenic modality in pulmonary arterial hypertension.

Impaired pulmonary angiogenesis plays a pivotal role in the progression of pulmonary arterial hypertension (PAH) and patient mortality, yet the molecular mechanisms driving this process remain enigmatic. Our study uncovered a striking connection between mitochondrial dysfunction (MD), caused by a humanized mutation in the NFU1 gene, and severely disrupted pulmonary angiogenesis in adult lungs. Restoring the bioavailability of the NFU1 downstream target, lipoic acid (LA), alleviated MD and angiogenic deficiency and rescued the progressive PAH phenotype in the NFU1G206C model. Notably, significant NFU1 expression and signaling insufficiencies were also identified in idiopathic PAH (iPAH) patients' lungs, emphasizing this study's relevance beyond NFU1 mutation cases. The remarkable improvement in mitochondrial function of PAH patient-derived pulmonary artery endothelial cells (PAECs) following LA supplementation introduces LA as a potential therapeutic approach. In conclusion, this study unveils a novel role for MD in dysregulated pulmonary angiogenesis and PAH manifestation, emphasizing the need to correct MD in PAH patients with unrecognized NFU1/LA deficiency.

Variant load of mitochondrial DNA in single human mesenchymal stem cells

Heteroplasmic mitochondrial DNA (mtDNA) variants accumulate as humans age, particularly in the stem-cell compartments, and are an important contributor to age-related disease. Mitochondrial dysfunction has been observed in osteoporosis and somatic mtDNA pathogenic variants have been observed in animal models of osteoporosis. However, this has never been assessed in the relevant human tissue. Mesenchymal stem cells (MSCs) are the progenitors to many cells of the musculoskeletal system and are critical to skeletal tissues and bone vitality. Investigating mtDNA in MSCs could provide novel insights into the role of mitochondrial dysfunction in osteoporosis. To determine if this is possible, we investigated the landscape of somatic mtDNA variation in MSCs through a combination of fluorescence-activated cell sorting and single-cell next-generation sequencing. Our data show that somatic heteroplasmic variants are present in individual patient-derived MSCs, can reach high heteroplasmic fractions and have the potential to be pathogenic. The identification of somatic heteroplasmic variants in MSCs of patients highlights the potential for mitochondrial dysfunction to contribute to the pathogenesis of osteoporosis.

Review on the Role of Mitochondrial Dysfunction in Septic Encephalopathy.

Septic Encephalopathy (SE) is a frequent and severe complication of sepsis, characterized by a range of neurocognitive impairments from mild confusion to deep coma. The underlying pathophysiology of SE involves systemic inflammation, neuroinflammation, blood-brain barrier (BBB) disruption, and mitochondrial dysfunction. Among these factors, mitochondrial dysfunction plays a pivotal role, contributing to impaired ATP production, increased reactive oxygen species (ROS) generation, and activation of apoptotic pathways, all of which exacerbate neuronal damage and cognitive deficits. Diagnosis of SE relies on clinical evaluation, neuroimaging, electroencephalography (EEG), and laboratory tests, though specific diagnostic markers are still lacking. Epidemiological data show SE is prevalent in intensive care unit (ICU) patients, especially those with severe sepsis or septic shock, with incidence rates varying widely depending on the population and diagnostic criteria used. Recent research highlights the importance of mitochondrial dynamics, including biogenesis, fission, and fusion, in the development of SE. Mitophagy, a selective form of autophagy that degrades damaged mitochondria, plays a critical role in maintaining mitochondrial health and protecting against dysfunction. Targeting mitochondrial pathways and enhancing mitophagy offers a promising therapeutic strategy to mitigate the effects of SE, reduce oxidative stress, prevent apoptosis, and support the resolution of neuroinflammation. Further research is essential to elucidate the mechanisms of mitochondrial dysfunction and mitophagy in SE and develop effective interventions to improve patient outcomes.

The role of mitochondrial dysfunction in the association between trace metals and QTc prolongation in the aged population

This study delves into the relationship between environmental metal exposure and QT interval corrected for heart rate (QTc) prolongation, a critical marker for cardiovascular risk in the elderly. Although the interplay between metal exposure and QTc prolongation is important for predicting sudden cardiac death, it remains underexplored. Our analysis of 6478 participants from the Shenzhen aging-related disorder cohort involved measuring urinary concentrations of 22 trace metals and using mitochondrial DNA copy number (mtDNA-CN) as an indicator of mitochondrial dysfunction. Utilizing Bayesian kernel machine regression, and structural equation modeling, we assessed the effects of mixed trace metals on QTc prolongation. Our findings indicated a direct association between certain metals (Sb, Cu, Zn) and a 7 % increase in QTc prolongation risk, while Li, V, and Rb were associated with a 5 % reduction in risk. Elevated levels of V, Ti, and Cr corresponded to higher mtDNA-CN. Notably, restricted cubic splines revealed a U-shaped, nonlinear relationship between mtDNA-CN and QTc prolongation. After adjusting for metal exposure, an inverse correlation was observed between mtDNA-CN and QTc prolongation, suggesting mitochondrial dysfunction as a partial mediator.

Unveiling differential gene co-expression networks and its effects on levodopa-induced dyskinesia

Levodopa-induced dyskinesia (LID) refers to involuntary motor movements of chronic use of levodopa in Parkinson's disease (PD) that negatively impact the overall well-being of people with this disease. The molecular mechanisms involved in LID were investigated through whole-blood transcriptomic analysis for differential gene expression and identification of new co-expression and differential co-expression networks. We found six differentially expressed genes in patients with LID, and 13 in patients without LID. We also identified 12 co-expressed genes exclusive to LID, and six exclusive hub genes involved in 23 gene-gene interactions in patients with LID. Convergently, we identified novel genes associated with PD and LID that play roles in mitochondrial dysfunction, dysregulation of lipid metabolism, and neuroinflammation. We observed significant changes in disease progression, consistent with previous findings of maladaptive plastic changes in the basal ganglia leading to the development of LID, including a chronic pro-inflammatory state in the brain.

SIRT1-mediated tunnelling nanotubes may be a potential intervention target for arsenic-induced hepatocyte senescence and liver damage

Arsenic, a widespread environmental poison, can cause significant liver damage upon exposure. Mitochondria are the most sensitive organelles to external factors. Dysfunctional mitochondria play a crucial role in cellular senescence and liver damage. Tunnelling nanotubes (TNTs), membrane structures formed between cells, with fibrous actin (F-actin) serving as the scaffold, facilitate mitochondrial transfer between cells. Notably, TNTs mediate the delivery of healthy mitochondria to damaged cells, thereby mitigating cellular damage. Although limited studies have suggested that F-actin may be modulated by the longevity gene SIRT1, the association between arsenic-induced liver damage and this mechanism remains unexplored. The findings of the current study indicate that arsenic suppresses SIRT1 and F-actin in the rat liver and MIHA cells, impeding the formation of TNTs and mitochondrial transfer between MIHA cells, thereby playing a pivotal role in mitochondrial dysfunction, cellular senescence and liver damage induced by arsenic. Notably, increasing SIRT1 levels effectively mitigated liver mitochondrial dysfunction and cellular senescence triggered by arsenic, highlighting SIRT1's crucial regulatory function. This research provides novel insights into the mechanisms underlying arsenic-induced liver damage, paving the way for the development of targeted preventive and therapeutic drugs to address arsenic-induced liver damage.

Roles of Mitochondrial Dysfunction in Diabetic Kidney Disease: New Perspectives from Mechanism to Therapy.

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes and the main cause of end-stage renal disease around the world. Mitochondria are the main organelles responsible for producing energy in cells and are closely involved in maintaining normal organ function. Studies have found that a high-sugar environment can damage glomeruli and tubules and trigger mitochondrial dysfunction. Meanwhile, animal experiments have shown that DKD symptoms are alleviated when mitochondrial damage is targeted, suggesting that mitochondrial dysfunction is inextricably linked to the development of DKD. This article describes the mechanisms of mitochondrial dysfunction and the progression and onset of DKD. The relationship between DKD and mitochondrial dysfunction is discussed. At the same time, the progress of DKD treatment targeting mitochondrial dysfunction is summarized. We hope to provide new insights into the progress and treatment of DKD.

Role of mitochondrial dysfunction and biogenesis in fibromyalgia syndrome: Molecular mechanism in central nervous system

A critical role for mitochondrial dysfunction has been shown in the pathogenesis of fibromyalgia. It is a chronic pain syndrome characterized by neuroinflammation and impaired oxidative balance in the central nervous system. Boswellia serrata (BS), a natural polyphenol, is a well-known able to influence the mitochondrial metabolism. The objective of this study was to evaluate the mitochondrial dysfunction and biogenesis in fibromyalgia and their modulation by BS. To induce the model reserpine (1 mg/Kg) was subcutaneously administered for three consecutive days and BS (100 mg/Kg) was given orally for twenty-one days. BS reduced pain like behaviors in reserpine-injected rats and the astrocytes activation in the dorsal horn of the spinal cord and prefrontal cortex that are recognized as key regions associated with the neuropathic pain. Vulnerability to neuroinflammation and impaired neuronal plasticity have been described as consequences of mitochondrial dysfunction. BS administration increased PGC-1α expression in the nucleus of spinal cord and brain tissues, promoting the expression of regulatory genes for mitochondrial biogenesis (NRF-1, Tfam and UCP2) and cellular antioxidant defence mechanisms (catalase, SOD2 and Prdx 3). According with these data BS reduced lipid peroxidation and the GSSG/GSH ratio and increased SOD activity in the same tissues. Our results also showed that BS administration mitigates cytochrome-c leakage by promoting mitochondrial function and supported the movement of PGC-1α protein into the nucleus restoring the quality control of mitochondria. Additionally, BS reduced Drp1 and Fis1, preventing both mitochondrial fission and cell death, and increased the expression of Mfn2 protein, facilitating mitochondrial fusion. Overall, our results showed important mitochondrial dysfunction in central nervous system in fibromyalgia syndrome and the role of BS in restoring mitochondrial dynamics.

Hippocampal transcriptome-wide association study and pathway analysis of mitochondrial solute carriers in Alzheimer’s disease

The etiopathogenesis of late-onset Alzheimer’s disease (AD) is increasingly recognized as the result of the combination of the aging process, toxic proteins, brain dysmetabolism, and genetic risks. Although the role of mitochondrial dysfunction in the pathogenesis of AD has been well-appreciated, the interaction between mitochondrial function and genetic variability in promoting dementia is still poorly understood. In this study, by tissue-specific transcriptome-wide association study (TWAS) and further meta-analysis, we examined the genetic association between mitochondrial solute carrier family (SLC25) genes and AD in three independent cohorts and identified three AD-susceptibility genes, including SLC25A10, SLC25A17, and SLC25A22. Integrative analysis using neuroimaging data and hippocampal TWAS-predicted gene expression of the three susceptibility genes showed an inverse correlation of SLC25A22 with hippocampal atrophy rate in AD patients, which outweighed the impacts of sex, age, and apolipoprotein E4 (ApoE4). Furthermore, SLC25A22 downregulation demonstrated an association with AD onset, as compared with the other two transcriptome-wide significant genes. Pathway and network analysis related hippocampal SLC25A22 downregulation to defects in neuronal function and development, echoing the enrichment of SLC25A22 expression in human glutamatergic neurons. The most parsimonious interpretation of the results is that we have identified AD-susceptibility genes in the SLC25 family through the prediction of hippocampal gene expression. Moreover, our findings mechanistically yield insight into the mitochondrial cascade hypothesis of AD and pave the way for the future development of diagnostic tools for the early prevention of AD from a perspective of precision medicine by targeting the mitochondria-related genes.

Coenzyme Q10 eyedrops conjugated with vitamin E TPGS alleviate neurodegeneration and mitochondrial dysfunction in the diabetic mouse retina.

Diabetic retinopathy (DR) is a leading cause of blindness and vision impairment worldwide and represents one of the most common complications among diabetic patients. Current treatment modalities for DR, including laser photocoagulation, intravitreal injection of corticosteroid, and anti-vascular endothelial growth factor (VEGF) agents, target primarily vascular lesions. However, these approaches are invasive and have several limitations, such as potential loss of visual function, retinal scars and cataract formation, and increased risk of ocular hypertension, vitreous hemorrhage, retinal detachment, and intraocular inflammation. Recent studies have suggested mitochondrial dysfunction as a pivotal factor leading to both the vascular and neural damage in DR. Given that Coenzyme Q10 (CoQ10) is a proven mitochondrial stabilizer with antioxidative properties, this study investigated the effect of CoQ10 eyedrops [in conjunction with vitamin E d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS)] on DR-induced neurodegeneration using a type 2 diabetes mouse model (C57BLKsJ-db/db mice). Utilizing a comprehensive electroretinography protocol, supported by immunohistochemistry, our results revealed that topical application of CoQ10 eyedrops conjugated with vitamin E TPGS produced a neuroprotective effect against diabetic-induced neurodegeneration by preserving the function and histology of various retinal neural cell types. Compared to the control group, mice treated with CoQ10 exhibited thicker outer and inner nuclear layers, higher densities of photoreceptor, cone cell, and rod-bipolar cell dendritic boutons, and reduced glial reactivity and microglial cell density. Additionally, the CoQ10 treatment significantly alleviated retinal levels of MMP-9 and enhanced mitochondrial function. These findings provide further insight into the role of mitochondrial dysfunction in the development of DR and suggest CoQ10 eyedrops, conjugated with vitamin E TPGS, as a potential complementary therapy for DR-related neuropathy.

AT-rich interactive domain-containing protein 1A (ARID1A) expression in placentas with late fetal growth restriction

BACKGROUND: Fetal growth restriction, which is considered as a multifactorial pathology, is a critical problem in obstetrics. The role of mitochondrial dysfunction in the pathogenesis of fetal growth restriction is not yet clear. However, it is known that it leads to oxidative stress, damage to cells and tissues, and dysfunction of key mechanisms for maintaining energy balance, the outcome of which may be the development of placental insufficiency. It is likely that AT-rich interactive domain-containing protein 1A (ARID1A) is involved in the development and function of the human placenta and may be an important marker in the development of fetal growth restriction. AIM: The aim of this study was to evaluate ARID1A protein expression in the placental villous tree in late fetal growth restriction. MATERIALS AND METHODS: This study included 50 placentas from children born at full-term gestation (37–40 weeks). The main study group consisted of placentas with late fetal growth restriction and without major extragenital pathology (n = 35). The control group comprised 15 placentas without fetal growth restriction (n = 15). Histological (n = 50) and immunohistochemical examinations of placentas (15 placentas in the main group and 10 placentas in the control group) using primary monoclonal antibodies to ARID1A were performed. RESULTS: In the study group with fetal growth restriction, chronic placental insufficiency was verified in all cases, dissociated chronic placental insufficiency (25 cases; 71.4%) being predominant, of which 23 cases (92%) were compensated, including 16 cases (69.6%) with moderate circulatory disorders. Hypoplastic chronic placental insufficiency was diagnosed in ten cases (28.6%) and was subcompensated with the presence of pronounced circulatory disorders. In the arteries of the stem villi, the ARID1A protein expression area did not differ between the study groups (p = 0.096), while in the veins in the stem villi with fetal growth restriction, we verified a decrease compared to control (p = 0.05). In the vascular bed of the villi with subcompensated dissociated chronic placental insufficiency, ARID1A protein expression was higher compared to hypoplastic chronic placental insufficiency (p = 0.041). CONCLUSIONS: Chronic placental insufficiency combined with fetal growth restriction is a serious complication of pregnancy with the development of structural and functional abnormalities and dysregulation of placental mechanisms. The ARIDA1A protein expression data obtained, depending on the degree of compensation for chronic placental insufficiency, may indicate the activation of compensatory metabolic mechanisms to maintain the functional activity of the placenta and preserve the viability of the fetus.

#1225 Lactate aggravates mitochondrial dysfunction via ALDH2 lactylation in acute kidney injury

Abstract Background and Aims Elevated lactate levels have been recognized as an independent risk factor in acute kidney injury (AKI) contributed by mitochondrial dysfunction. We previously proved the crucial role of acetaldehyde dehydrogenase 2 (ALDH2) in AKI but not focused on the lactate and lactylation of ALDH2. Method We first established a maleic acid (MA) induced AKI model (MA-AKI) in C57BL/6J mice, administrating 2-DG i.p. (a glycolysis inhibitor) or oxamate (a lactate dehydrogenase A inhibitor) to suppress the lactate production. We measured the renal function, mitochondrial function, and lactate in serum and urine, then evaluated the ALDH2 lactylation by co-immunoprecipitation assays, and identified the specific lactation site by mass spectrum. The role of ALDH2 lactylation was explored through point mutation in HEK293 cells. Furthermore, an ALDH2 lactylation eraser was identified, and its function was elucidated in mice and HK-2 cells. Results The elevated lactate in the kidney, serum, and urine showed a significant positive correlation to the serum creatinine (Scr, R2 = 0.83, P &amp;lt; 0.0001) in MA-induced mice. Both 2-DG and oxamate partly abolished the Scr increasing and the proximal tubular histopathological injuries. Increased pan-lactylation in AKI mice was effectively inhibited by oxamate, parallel with increased ALDH2 lactylation in MA-stimulated HK-2 cells. Mass spectrometry identified a single lactylate lysine residue in ALDH2 (K52). The introduction of a point mutation (K52 to R) in ALDH2, mimicking the delactylated state, led to partial recovery of ALDH2 activity (1.11 ± 0.07 vs. 0.68 ± 0.15, P = 0.0029) and mitochondrial function in MA-stimulated HK-2 cells. Additionally, sirt3 was identified as an ALDH2 lactylation eraser, and Honokiol (a sirt3 activator) demonstrated enhanced renal function and mitigation of mitochondrial dysfunction in both MA-induced mice and HK-2 cells. Conclusion Lactate played a crucial role in mitochondrial dysfunction in AKI partly via induction of ALDH2 lactylation, which shed light on the potential target for the therapy.

Research Progress in the Role of Mitochondrial Dysfunction in Endometriosis-Associated Infertility

Endometriosis (EMT), a common benign gynecological disease, is a leading cause of infertility in women. EMT affects female fertility in various aspects. However, the underlying mechanisms have not been fully elucidated. Mitochondria are known as the "powerhouse" of a cell. They play pivotal roles in the physiological processes of cellular energy metabolism, calcium homeostasis, oxidative stress, autophagy, the regulation of cell cycle, and cell death, and are involved in the pathophysiology of many diseases. Cellular mitochondria are highly dynamic, continuously undergoing cyclic fission and fusion to meet the demands of cellular activities. Balanced mitochondrial dynamics are critical for maintaining normal reproductive function in women. In addition, mitochondria are the major source of reactive oxygen species (ROS). Cell damage, cell death, and fibrosis mediated by the imbalance in the oxidative-antioxidant system in EMT patients lead to decreased oocyte quality and ovarian reserve. Currently, the treatment of EMT-associated infertility remains a challenging and controversial topic. We herein reviewed the latest findings on the role of mitochondrial dysfunction in EMT-associated infertility and the potential therapeutic targets.