Biochemistry (Moscow)最新文献

{"title":"Glycosylase Base Editors: New Tools for Genome Editing","authors":"Liliya M. Kulishova,&nbsp;Dmitry O. Zharkov","doi":"10.1134/S0006297926601073","DOIUrl":"10.1134/S0006297926601073","url":null,"abstract":"<p>Genome editing using the CRISPR/Cas9 system has become a staple of modern genome manipulation. In its original form, editing involved introducing double-strand breaks into DNA, which can cause genomic instability. The appearance of the first base editors in 2016 expanded the range of editing technologies and enabled single-nucleotide changes to be introduced into the genome through deamination of nucleobases, bypassing the double-strand break stage. Further development of base editors involves the incorporation of additional modules, DNA glycosylases, that can remove modified or even normal nucleobases and create non-instructive apurinic/apyrimidinic sites in DNA, significantly expanding the range of available single-nucleotide substitutions. This review examines the operating principles of the glycosylase base editors, the main limitations of these genome manipulation tools, and promising areas for the development of this technology.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"91 7","pages":"1093 - 1113"},"PeriodicalIF":2.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148628482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Secreted Cyclophilin A Induces M1 and M2 Macrophage Polarization in the THP-1 Model in vitro","authors":"Anastasiia A. Kalinina,&nbsp;Marina V. Kubekina,&nbsp;Maria A. Zamkova,&nbsp;Nadezhda A. Persiyantseva,&nbsp;Alexandra V. Bruter,&nbsp;Dmitry B. Kazansky,&nbsp;Ludmila M. Khromykh","doi":"10.1134/S0006297926600432","DOIUrl":"10.1134/S0006297926600432","url":null,"abstract":"<p>Fate of monocytes that migrate into tissues is determined by various mediators at the site of inflammation. The microenvironment governs monocyte differentiation and polarization into macrophages, which acquire different surface markers and opposite functions. Secreted cyclophilin A (CypA) is a pro-inflammatory factor and a component of the monocyte humoral microenvironment. In these studies, effects of recombinant human CypA (rhCypA) on differentiation of human monocytic cells were evaluated in the THP-1 <i>in vitro</i> model. RhCypA induced polarization of M1 macrophages in the early stages of THP-1 ontogenesis without additional stimuli, whereas it promoted M2 polarization only in the cells differentiated to M0 monocytes and in the presence of IL-4 and IL-13. Under conditions of M2 induction, rhCypA significantly upregulated expression of the genes of characteristic M2 markers CD163 and IL-10 in the THP-1 cells, and decreased the level of p38 MAP kinase activation, suggesting diminished pro-inflammatory activity of the generated cells. The RhCypA-induced M1 and M2 macrophages inhibited proliferation of activated CD4+ T cells via direct cell-cell contact. These findings suggested that secreted CypA could induce generation of suppressor M2 macrophages and/or myeloid-derived suppressor cells at the site of inflammation during infection or cancer progression. This new immunoregulatory effect of rhCypA could be of particular clinical relevance for the development of strategies for controlling chronic inflammation and reprogramming the tumor microenvironment.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"91 7","pages":"1230 - 1240"},"PeriodicalIF":2.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1134/S0006297926600432.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148628483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemically Induced Dimerization Systems: From FKBP/FRB Engineering to Expanded Biological Applications","authors":"Hui Yuan,&nbsp;Shuo Lin,&nbsp;Ziyi Lin,&nbsp;Shuangpeng Li,&nbsp;Xia Zuo,&nbsp;Haihua Yin,&nbsp;Ruilin Cheng,&nbsp;Yuqian Tang,&nbsp;Zihao Luo,&nbsp;Min Chen,&nbsp;Qingjian Zou","doi":"10.1134/S0006297926600705","DOIUrl":"10.1134/S0006297926600705","url":null,"abstract":"<p>The FKBP-based chemically induced dimerization (CID) technology is a fundamental tool for spatiotemporal precise modulation of protein functions in living cells, widely used in gene editing, protein function regulation, disease therapy, and drug development. However, its widespread application is limited by the inherent drawbacks including issues with immunosuppressive activity, stability, reversibility, and <i>in vivo</i> delivery. Recent years have seen remarkable progress in addressing these challenges: orthogonalization strategies eliminate immunosuppressive effects, fast-dissociating ligands and optogenetic systems enable reversible regulation, and protein engineering optimizes the FKBP/FRB domains to enhance stability and reduce immunogenicity. Moreover, integration with novel delivery technologies broadens its application scope greatly. This review summarizes the key optimization strategies and innovative applications of this technology in the cutting-edge biological research, aiming to reference the development of next-generation chemogenetic tools with higher precision, better safety, and greater application potential.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"91 7","pages":"1051 - 1072"},"PeriodicalIF":2.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148628484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Levels of Neurotrophic Factors in the Rat Hippocampus in the Acute Period after Middle Cerebral Artery Occlusion Are Associated with the Hypothalamic–Pituitary–Adrenal Axis Activation","authors":"Mikhail V. Onufriev,&nbsp;Yulia V. Moiseeva,&nbsp;Margarita R. Novikova,&nbsp;Pavel A. Kostryukov,&nbsp;Natalia V. Gulyaeva","doi":"10.1134/S0006297925604162","DOIUrl":"10.1134/S0006297925604162","url":null,"abstract":"<p>Ischemic stroke is one of the most prevalent neurological disorders, with primary injury typically localized to the neocortex. However, secondary damage often extends to anatomically distant regions, particularly the hippocampus. One of the early neuroendocrine responses to cerebral ischemia is activation of the hypothalamic–pituitary–adrenal (HPA) axis. Increased release of corticosterone (CORT) by the adrenal glands into the bloodstream leads to its accumulation in the hippocampus. We hypothesize that this process may contribute to the hippocampal damage and underlie delayed cognitive and affective impairments following stroke. To test this, we investigated the levels of neurotrophic factors reflecting the neuroprotective potential of the hippocampus using two established middle cerebral artery occlusion (MCAO) models that differ in their effects on CORT production: the Koizumi et al. (1986) model (MCAO1) and the Longa et al. (1989) model (MCAO2). Although both models produced comparable neurological deficits, mortality rates, and infarct volumes, they differed markedly in endocrine and hippocampal responses. Significant increases in circulating CORT and its accumulation in both ipsilateral and contralateral hippocampus were observed only in MCAO1. Moreover, correlations between the CORT levels (in the blood and hippocampus) and both rat body weight and neurological deficit were stronger in MCAO1 than in MCAO2. In both acute models, brain-derived neurotrophic factor (BDNF) levels were elevated in the ipsilateral hippocampus, whereas the content of glial cell line-derived neurotrophic factor (GDNF) remained unchanged. In contrast, ciliary neurotrophic factor (CNTF) increased in the ipsilateral hippocampus only in MCAO2. These findings suggest that differential activation of the HPA axis and consequent variations in corticosteroid signaling in the hippocampus selectively modulate the neurotrophic response during the acute phase following MCAO.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"91 7","pages":"1187 - 1199"},"PeriodicalIF":2.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1134/S0006297925604162.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148628480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aptamer Sensors for Inflammaging Biomarkers: Principles of Molecular Recognition, Analytical Platforms, and Unaddressed Targets","authors":"Nataliya O. Kudryashova,&nbsp;Igor V. Dobrokhotov,&nbsp;Elizaveta S. Ershova,&nbsp;Alexey A. Moskalev","doi":"10.1134/S0006297926601127","DOIUrl":"10.1134/S0006297926601127","url":null,"abstract":"<p>Inflammaging, a chronic, low-grade systemic inflammatory state that develops with advancing age, is one of the key drivers of age-associated pathology and promotes the emergence of the senescence-associated secretory phenotype (SASP). Timely quantitative monitoring of pro-inflammatory and SASP-associated biomarkers therefore demands highly sensitive analytical platforms capable of reliable performance in complex biological matrices. Aptamer-based biosensors (aptasensors), which employ short single-stranded oligonucleotides offering high affinity and specificity for molecular recognition, have emerged as promising alternatives and complements to conventional antibody-based assays. This review provides a comprehensive overview of aptasensor platforms developed for biomarkers of age-associated inflammation and identifies molecular targets of relevance to aging biology that remain unexplored. Following PRISMA guidelines, a systematic literature search of the PubMed database was conducted for studies published between 2020 and 2026. A total of 221 original studies met the inclusion criteria and were qualitatively analyzed, encompassing 47 biomarkers and seven classes of analytical platforms. The analysis revealed a pronounced research bias: 73% of published studies focused on just five well-established biomarkers – VEGF, CRP, IL-6, IFN-γ, and TNF-α – leaving many biomarkers with recognized relevance to aging without any aptasensor-based detection strategy. The review also discusses the molecular mechanisms underlying aptamer–target recognition, recent advances in SELEX technologies, and chemical modifications, including 2′-F nucleotides, locked nucleic acids (LNAs), SOMAmers, and spiegelmers, that enhance aptamer stability and affinity. Finally, we discuss the principal obstacles limiting clinical translation of aptamer technologies and propose priorities for future research, including multiplex ratiometric aptasensors for SASP cytokine profiling, aptamer-based extracellular vesicle capture as a route to intracellular biomarkers, and novel strategies for generating aptamers against currently inaccessible molecular targets.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"91 7","pages":"1114 - 1136"},"PeriodicalIF":2.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148628688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of the C.886C>T Mutation in the Mouse Tyrosine Hydroxylase Gene on Behavior and Dopamine System of the Brain","authors":"Ismail Alsalloum,&nbsp;Ilya A. Rakhov,&nbsp;Polina D. Komleva,&nbsp;Valentina N. Kuranova,&nbsp;Anastasia E. Bastrikova,&nbsp;Alexander V. Kulikov,&nbsp;Darya V. Bazovkina","doi":"10.1134/S0006297926600171","DOIUrl":"10.1134/S0006297926600171","url":null,"abstract":"<p>Dopamine (DA) is a critical regulator of physiological functions and adaptive behavior. The enzyme tyrosine hydroxylase (TH) catalyzes hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (DOPA), which is the first and rate-limiting step in the DA biosynthesis. Mutations in the human <i>TH</i> gene have been linked to dystonia, catalepsy, and catatonia. In the present study, we examined how the functional mutation c.886C&gt;T in the <i>Th</i> gene affects the brain DA system and behavior in mice. The C allele – which confers high TH enzyme activity – was introgressed from the <i>Mus musculus castaneus</i> subspecies into the C57BL/6 inbred background, yielding three congenic genotypes: B6-886CC, B6-886CT, and B6-886TT. Males of each genotype were evaluated in a battery of behavioral tests; and TH activity, levels of DA and DA metabolites, norepinephrine, and mRNA levels of the key DA system genes were measured across the brain structures. The three genotypes did not differ in body weight, locomotor activity, motor coordination, or cognitive performance. However, the B6-886TT mice showed significantly reduced exploratory activity in the open field test relative to the B6-886CC and B6-886CT animals. The B6-886TT mice also exhibited lower TH activity and DA content in the midbrain, and reduced DOPAC levels in the hypothalamus, compared to the B6-886CC animals. The c.886C&gt;T mutation had no detectable effect on expression of the genes encoding key DA metabolic enzymes or DA receptors. In a separate experiment, we genotyped 80 DNA samples from the <i>Mus musculus</i> collected across natural populations in Russia. The C and T allele frequencies were 0.981 and 0.019, respectively, suggesting that the T allele may be subject to negative natural selection.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"91 7","pages":"1200 - 1215"},"PeriodicalIF":2.1,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148628721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetic Retinopathy: From Molecular Mechanisms to Modern Therapy","authors":"Natalia G. Shebardina,&nbsp;Kristina A. Kazakova,&nbsp;Timur A. Asaevich,&nbsp;Sofia A. Belolipskaia,&nbsp;Ivan V. Rodionov,&nbsp;Sanchay S. Tulush,&nbsp;Mikhail L. Shishkin,&nbsp;Andrey R. Komarov,&nbsp;Olga A. Krasienko,&nbsp;Elizaveta S. Gromova,&nbsp;Andrey A. Zamyatnin Jr.,&nbsp;Anastasia M. Moisenovich,&nbsp;Evgeni Yu. Zernii","doi":"10.1134/S000629792660105X","DOIUrl":"10.1134/S000629792660105X","url":null,"abstract":"<p>Diabetic retinopathy (DR) remains one of the leading causes of vision loss. Its development is driven by complex interconnected pathophysiological mechanisms triggered by chronic hyperglycemia. Traditional diagnostic approaches, which rely on detecting visible microangiopathies, often identify the disease only after significant and progressive retinal damage had already occurred. Consequently, current therapeutic strategies are largely focused on managing advanced, proliferative stages of DR. A major direction in modern ophthalmology is the shift toward identifying and intervening at stages that precede clinical DR manifestations. This review presents current data on the pathogenesis and molecular mechanisms of DR, discusses associated biochemical alterations revealed through multi-omics approaches, and examines methods for preclinical diagnostics, innovative therapeutic strategies, and novel targets for early pathogenetic intervention. Overall, the evidence suggests that that effective treatment options for DR might include multi-target therapeutic approaches extending beyond the blockade of angiogenesis and aimed at addressing metabolic, inflammatory, and oxidative disorders causing neurodegeneration and vascular dysfunction.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"91 8","pages":"1319 - 1340"},"PeriodicalIF":2.1,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148837828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective Effect of Subconjunctival Melatonin Injections in 6-Hydroxydopamine-Induced Neurotoxic Eye Damage","authors":"Tatyana A. Pavlenko,&nbsp;Natalya B. Chesnokova,&nbsp;Olga A. Lisovskaya,&nbsp;Olga V. Beznos,&nbsp;Andrey V. Grigoryev","doi":"10.1134/S0006297925603880","DOIUrl":"10.1134/S0006297925603880","url":null,"abstract":"<p>The search for new effective methods of neuroprotection is relevant for the treatment of a wide range of common eye diseases such as age-related macular degeneration, glaucoma, and diabetic retinopathy. Using a rabbit model of neurotoxic eye damage induced by intravitreal injection of the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA), we studied the effect of subconjunctival injections of 0.1% melatonin solution on pathophysiological and biochemical processes in the eye. Administration of 6-OHDA caused destruction of the retinal pigment epithelium, narrowing of retinal vessels, hemorrhages, decrease in ocular blood flow, and intraocular pressure, as well as reduced activity of α₂-macroglobulin and concentrations of matrix metalloproteinase-9 and angiotensin-converting enzyme in the aqueous humor, vitreous body, and retina. Subconjunctival melatonin injections over 9 days resulted in the 2-fold on average reduction of the area of retinal damage, and normalization of the minute volume of ocular blood flow and intraocular pressure. On day 14, an increase in the α₂-macroglobulin activity in the aqueous humor (0.66 ± 0.19 vs. 0.49 ± 0.13 nmol/min per 1 mg protein) and vitreous body (0.50 ± 0.15 vs. 0.21 ± 0.07 nmol/min per 1 mg protein, <i>p</i> &lt; 0.05) was observed, along with a decrease in the matrix metalloproteinase-9 concentration (118.4 ± 34.6 vs. 524.3 ± 163.2 ng/mg, <i>p</i> &lt; 0.05) and angiotensin-converting enzyme concentration (371.0 ± 52.1 vs. 596.1 ± 171.5 ng/mg, <i>p</i> &lt; 0.05) in the retina. This indicates reduction in the intensity of inflammation and vascular wall permeability. Melatonin could be considered a promising neuroprotective component in the complex therapy of retinal diseases.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"91 8","pages":"1396 - 1405"},"PeriodicalIF":2.1,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148837829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroinflammation, Glia–Neuron Crosstalk, and Energy Metabolism in Alcohol Use Disorder","authors":"Valentin Yu. Skryabin,&nbsp;Svetlana I. Sokolova,&nbsp;Anton V. Masyakin","doi":"10.1134/S0006297925604149","DOIUrl":"10.1134/S0006297925604149","url":null,"abstract":"<p>Chronic alcohol and other psychoactive substance use is accompanied not only by disturbances in classical neurotransmitter systems but also by persistent activation of innate and adaptive immunity, leading to neuroinflammation. This review summarizes experimental and clinical data on how microglia and astrocytes act as central mediators at the intersection of immune, metabolic, and neuronal processes in alcohol-related disorders. We discuss Toll-like receptor 4 (TLR4)-dependent pathways, activation of the NLRP3 inflammasome, impaired glutamate clearance, metabolic “reprogramming” of glia, and mitochondrial dysfunction. These changes lead to energy deficiency, oxidative stress, and persistent remodeling of reward, stress, and cognitive control networks. Particular attention is given to the impact of neuroinflammation on dopaminergic, glutamatergic, GABAergic, and serotonergic neurotransmission, including the shift of tryptophan metabolism toward the kynurenine pathway. We also consider the role of the gut–liver–brain axis, dysbiosis, endotoxemia, systemic inflammation, and impaired production of short-chain fatty acids in maintaining neuroimmune–metabolic stress. Contribution of hepatic and adipose tissue to the formation of a chronic inflammatory milieu and its effect on blood–brain barrier (BBB) permeability is discussed. Based on the combined data, the authors propose an integrative model of dependence as a state arising at the intersection of disrupted neural signaling, disordered energy metabolism, and altered inter-organ communication. Promising therapeutic targets are outlined, including normalization of glial function, modulation of the gut microbiota, reduction of systemic inflammation, and targeting energy metabolism. The need to develop biomarker panels to identify subgroups of patients with the pronounced neuroinflammatory burden is emphasized.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"91 “Interaction","pages":"847 - 866"},"PeriodicalIF":2.1,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay between Neuronal Metabolism and Signaling in Model Systems with Impaired α-Ketoglutarate Dehydrogenase Complex Activity","authors":"Márton Kokas,&nbsp;Attila Ambrus,&nbsp;László Tretter,&nbsp;Tímea Komlódi","doi":"10.1134/S0006297926600663","DOIUrl":"10.1134/S0006297926600663","url":null,"abstract":"<p>The α-ketoglutarate dehydrogenase complex (KGDHC) serves as a master regulator of cell’s molecular machinery. Beyond its classical role as a rate-limiting enzyme in the tricarboxylic acid (TCA) cycle, KGDHC has emerged as a critical redox sensor that can act as both a source and a target of reactive oxygen species (ROS), thereby regulating cellular redox homeostasis. This review summarizes evidence from genetically modified animal models and cell culture studies demonstrating that compromised KGDHC activity affects neuronal metabolism, redox homeostasis, and cellular signaling. KGDHC dysfunction causes mitochondrial failure, resulting in reduced ATP synthesis and activation of AMP-activated protein kinase (AMPK). Although inhibition of KGDHC reduces mitochondrial ROS formation, it also disrupts physiological ROS-dependent signaling mechanisms. In KGDHC-deficient mice, impaired ROS signaling and energy deficit decrease brain adaptability, increase susceptibility to neurotoxins, and disrupt crucial pathways by downregulating PGC-1α and Nrf2. These alterations result in suppression of antioxidant defences and lead to neuronal death in the hippocampus and memory impairment. Moreover, KGDHC dysfunction induces mitochondrial fragmentation and is strongly linked to excitotoxicity, further accelerating neuronal dysfunction. As observed in heterozygous models, even partial KGDHC deficiency can exacerbate persisting cellular and mitochondrial defects, leading to the development of more severe pathological conditions.</p>","PeriodicalId":483,"journal":{"name":"Biochemistry (Moscow)","volume":"91 “Interaction","pages":"893 - 909"},"PeriodicalIF":2.1,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}