Mitochondria and Brain Disease: A Comprehensive Review of Pathological Mechanisms and Therapeutic Opportunities

Biomedicines, Journal Year: 2023, Volume and Issue: 11(9), P. 2488 - 2488

Published: Sept. 7, 2023

Mitochondria play a vital role in maintaining cellular energy homeostasis, regulating apoptosis, and controlling redox signaling. Dysfunction of mitochondria has been implicated the pathogenesis various brain diseases, including neurodegenerative disorders, stroke, psychiatric illnesses. This review paper provides comprehensive overview intricate relationship between disease, focusing on underlying pathological mechanisms exploring potential therapeutic opportunities. The covers key topics such as mitochondrial DNA mutations, impaired oxidative phosphorylation, dynamics, calcium dysregulation, reactive oxygen species generation context disease. Additionally, it discusses emerging strategies targeting dysfunction, protective agents, metabolic modulators, gene therapy approaches. By critically analysing existing literature recent advancements, this aims to enhance our understanding multifaceted disease shed light novel interventions.

Language: Английский

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Potential role and therapeutic implications of glutathione peroxidase 4 in the treatment of Alzheimer’s disease

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(3), P. 613 - 631

Published: March 1, 2024

Alzheimer’s disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, cure for has not yet been found. Oxidative stress mediates excessive oxidative responses, its involvement in pathogenesis as primary or secondary pathological event widely accepted. As member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With discovery ferroptosis, central role anti-lipid peroxidation several diseases, including disease, received widespread attention. Increasing evidence suggests that expression inhibited brain, resulting stress, inflammation, apoptosis, which are closely associated damage disease. Several therapeutic approaches, such small molecule drugs, natural plant products, non-pharmacological treatments, ameliorate cognitive function by promoting enhancing activity. Therefore, upregulation may be promising strategy treatment This review provides overview gene structure, biological functions, regulatory mechanisms 4, discussion on important events related summary advances small-molecule therapies targeting Most prior studies this subject used animal models, relevant clinical lacking. Future trials required validate effects strategies

Language: Английский

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Targeting tau in Alzheimer's disease: from mechanisms to clinical therapy

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 19(7), P. 1489 - 1498

Published: Sept. 22, 2023

Abstract Alzheimer's disease is the most prevalent neurodegenerative affecting older adults. Primary features of include extracellular aggregation amyloid-β plaques and accumulation neurofibrillary tangles, formed by tau protein, in cells. While there are amyloid-β-targeting therapies for treatment disease, these costly exhibit potential negative side effects. Mounting evidence suggests significant involvement protein disease-related neurodegeneration. As an important microtubule-associated plays role maintaining stability neuronal microtubules promoting axonal growth. In fact, clinical studies have shown that abnormal phosphorylation occurs before brain. Various therapeutic strategies targeting begun to emerge, considered possible methods prevent treat disease. Specifically, abnormalities post-translational modifications including aberrant phosphorylation, ubiquitination, small ubiquitin-like modifier (SUMO)ylation, acetylation, truncation, contribute its microtubule dissociation, misfolding, subcellular missorting. This causes mitochondrial damage, synaptic impairments, gliosis, neuroinflammation, eventually leading neurodegeneration cognitive deficits. review summarizes recent findings on underlying mechanisms onset progression discusses tau-targeted

Language: Английский

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Mitochondria-Targeted Delivery Strategy of Dual-Loaded Liposomes for Alzheimer’s Disease Therapy

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(13), P. 10494 - 10494

Published: June 22, 2023

Liposomes modified with tetradecyltriphenylphosphonium bromide dual loading of α-tocopherol and donepezil hydrochloride were successfully designed for intranasal administration. Physicochemical characteristics cationic liposomes such as the hydrodynamic diameter, zeta potential, polydispersity index within range from 105 to 115 nm, +10 +23 mV, 0.1 0.2, respectively. In vitro release curves analyzed using Korsmeyer-Peppas, Higuchi, First-Order, Zero-Order kinetic models. Nanocontainers surfactant statistically better penetrate into mitochondria rat motoneurons. Imaging brain slices revealed penetration nanocarriers brain. Experiments on transgenic mice an Alzheimer's disease model (APP/PS1) demonstrated that administration 21 days resulted in enhanced learning abilities a reduction formation rate Aβ plaques entorhinal cortex hippocampus

Language: Английский

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Natural antioxidants that act against Alzheimer’s disease through modulation of the NRF2 pathway: a focus on their molecular mechanisms of action

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 14

Published: July 3, 2023

Characterized by a complex pathophysiology that includes the intraneuronal formation of neurofibrillary tangles and extracellular deposition β-amyloid plaques, Alzheimer’s disease (AD) is terminal neurodegenerative causes dementia in older adults. Oxidative stress brain considered as one contributing factors to pathogenesis AD, thus, antioxidants have attracted much interest potential therapeutic agents against disorder. Natural are typically characterized low acute chronic toxicity, which facilitates their application. One important molecular target for beneficial effects natural nuclear factor erythroid-derived 2-related 2 (NFE2L2/NRF2). NRF2 key transcription orchestrates cellular antioxidant response through regulating expression oxidative stress-related genes harboring element (ARE) promoters. Indeed, case excessive damage, migrates nucleus binds ARE, activating protector genes. There increasing evidence implicated AD pathology dysfunction altered localization, renders it AD. Thus, this review summarizes most recent (2018-2023) advances on NRF2-modulating activity observed vitro animal models. This information will help elucidate mechanisms governing such phytochemicals highlight common diseases,

Language: Английский

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Epilepsy: Mitochondrial connections to the ‘Sacred’ disease

Mitochondrion, Journal Year: 2023, Volume and Issue: 72, P. 84 - 101

Published: Aug. 13, 2023

Over 65 million people suffer from recurrent, unprovoked seizures. The lack of validated biomarkers specific for myriad forms epilepsy makes diagnosis challenging. Diagnosis and monitoring childhood add to the need non-invasive biomarkers, especially when evaluating antiseizure medications. Although underlying mechanisms epileptogenesis are not fully understood, evidence mitochondrial involvement is substantial. Seizures affect 35%-60% patients diagnosed with diseases. Mitochondrial dysfunction pathophysiological in various epilepsies, including those non-mitochondrial origin. Decreased ATP production caused by malfunctioning brain cell mitochondria leads altered neuronal bioenergetics, metabolism neurological complications, Iron-dependent lipid peroxidation initiates ferroptosis, a death pathway that aligns morphology found neurodegenerative diseases (NDDs). Studies mouse genetic models seizure phenotypes where function an essential selenoprotein (GPX4) targeted suggest roles ferroptosis epilepsy. GPX4 pivotal NDDs, selenium protects interneurons ferroptosis. Selenium central nervous system micronutrient trace element. Low serum concentrations other elements minerals, iron, noted diagnosing supplements alleviate intractable seizures children reduced GPX activity. Copper cuproptosis, like iron link NDDs. Connecting these mechanistic pathways selenoproteins provides new insights into treating seizures, pointing using medicines prodrugs lipoic acid treat potential alternative therapeutic approaches transcranial magnetic stimulation (transcranial), photobiomodulation vagus nerve stimulation.

Language: Английский

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DNA repair deficiencies and neurodegeneration

DNA repair, Journal Year: 2024, Volume and Issue: 138, P. 103679 - 103679

Published: April 16, 2024

Neurodegenerative diseases are the second most prevalent cause of death in industrialized countries. Alzheimer's Disease is widespread and also acknowledged form dementia today. Together with Parkinson's they account for over 90 % cases neurodegenerative disorders caused by proteopathies. Far less known pathologies DNA repair deficiency syndromes. Such like Cockayne - or Werner Syndrome described as progeroid syndromes that premature ageing affected persons, there clear implications such neurologic dysfunction degeneration. In this review, we aim to draw attention on commonalities between proteopathy-associated neurodegeneration defects discuss how mitochondria implicated development both disorder classes. Furthermore, highlight nematodes a valuable indispensable model organism study conserved processes fast-forward manner.

Language: Английский

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Comparing In vitro Protein Aggregation Modelling Using Strategies Relevant to Neuropathologies

Cellular and Molecular Neurobiology, Journal Year: 2025, Volume and Issue: 45(1)

Published: March 13, 2025

Abstract Protein aggregation is remarkably associated with several neuropathologies, including Alzheimer´s (AD) and Parkinson´s disease (PD). The first characterized by hyperphosphorylated tau protein Aβ peptide deposition, thus forming intracellular neurofibrillary tangles extracellular senile plaques, respectively; while, in PD, α-synuclein aggregates deposits as Lewy bodies. Considerable research has focused on developing models to be explored tools. In the present work, four vitro for studying were studied compared, namely treatment with: toxic Aβ1-42 peptide, isoflavone rotenone, ATP synthase inhibitor oligomycin, proteosome MG-132. All treatments result aggregation-relevant events human neural SH-SY5Y cell line, but significant model-dependent differences observed. terms of promoting aggregate formation, MG-132 provoked greatest effect, only was an increase HSP-70 chaperone expression. fact, type formed appear dependent employed, supports hypothesis that exposure a relevant AD model, rotenone valid model PD. Furthermore, results revealed phosphorylation formation expected, co-localized induction model. summary, different molecular processes, from overall specific proteostatic modulation, can induced using distinct modelling strategies, these used study protein-aggregation-related processes neuropathologies.

Language: Английский

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SIRT4 in ageing

Biogerontology, Journal Year: 2023, Volume and Issue: 24(3), P. 347 - 362

Published: April 17, 2023

Language: Английский

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Synthesis of Veliparib Prodrugs and Determination of Drug-Release-Dependent PARP-1 Inhibition

ACS Medicinal Chemistry Letters, Journal Year: 2023, Volume and Issue: 14(5), P. 652 - 657

Published: April 24, 2023

Poly(ADP-ribose) polymerase (PARP) plays a key role in repairing DNA damage, and several PARP inhibitors have been approved as treatments BRCA1/2 mutated breast ovarian cancers. Mounting evidence also supports their application neuroprotective agents since overactivation compromises the mitochondrial homeostasis by consumption of NAD+ reserves, leading to an increase reactive oxygen nitrogen species spike intracellular Ca2+ levels. Herein, we present synthesis preliminary evaluation new mitochondria-targeting inhibitor prodrugs (±)-veliparib, with goal advance potential properties without impairing repair damaged nucleus.

Language: Английский

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