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Frontiers in Bioscience (Landmark... Jan 2024Parkinson's disease (PD) is characterized by the degeneration of the dopaminergic neurons of the corpus striatum, which can be caused by the disruption of processes of... (Review)
Review
Parkinson's disease (PD) is characterized by the degeneration of the dopaminergic neurons of the corpus striatum, which can be caused by the disruption of processes of mitochondrial homeostasis, including mitophagy, mitochondrial fusion and division, mitochondrial transport, accumulation of reactive oxygen species (ROS), and calcium signaling. Dopaminergic neurons are particularly vulnerable to mitochondrial dysfunction due to their polarized and expanded structure and high bioenergy needs. The molecular basis of these disorders is manifested in mutations of mitochondrial homeostasis proteins. Understanding the functions of these proteins and the disorders caused by these mutations can be used to create therapeutics for the treatment of PD and diagnostic biomarkers of PD. A comprehensive analysis of research papers to identify promising therapeutic targets and drug compounds that target them, as well as biomarkers of mitochondrial dysfunction that can be used in clinical practice for the treatment of PD has been conducted in the current review. This practical approach advantageously emphasizes the difference between this work and other reviews on similar topics. The selection of articles in this review was carried out using the following keyword searches in scientific databases: PubMed, Google Scholar, NSBI, and Cochrane. Next, the most relevant and promising studies were re-selected.
Topics: Humans; Parkinson Disease; Mitochondria; Reactive Oxygen Species; Mitochondrial Proteins; Mitochondrial Diseases; Biomarkers
PubMed: 38287806
DOI: 10.31083/j.fbl2901036 -
International Journal of Molecular... Feb 2024Mitochondrial dysfunction, a feature of heart failure, leads to a progressive decline in bioenergetic reserve capacity, consisting in a shift of energy production from... (Review)
Review
Mitochondrial dysfunction, a feature of heart failure, leads to a progressive decline in bioenergetic reserve capacity, consisting in a shift of energy production from mitochondrial fatty acid oxidation to glycolytic pathways. This adaptive process of cardiomyocytes does not represent an effective strategy to increase the energy supply and to restore the energy homeostasis in heart failure, thus contributing to a vicious circle and to disease progression. The increased oxidative stress causes cardiomyocyte apoptosis, dysregulation of calcium homeostasis, damage of proteins and lipids, leakage of mitochondrial DNA, and inflammatory responses, finally stimulating different signaling pathways which lead to cardiac remodeling and failure. Furthermore, the parallel neurohormonal dysregulation with angiotensin II, endothelin-1, and sympatho-adrenergic overactivation, which occurs in heart failure, stimulates ventricular cardiomyocyte hypertrophy and aggravates the cellular damage. In this review, we will discuss the pathophysiological mechanisms related to mitochondrial dysfunction, which are mainly dependent on increased oxidative stress and perturbation of the dynamics of membrane potential and are associated with heart failure development and progression. We will also provide an overview of the potential implication of mitochondria as an attractive therapeutic target in the management and recovery process in heart failure.
Topics: Humans; Mitochondria, Heart; Heart Failure; Cardiomegaly; Myocytes, Cardiac; Oxidative Stress; Mitochondrial Diseases
PubMed: 38473911
DOI: 10.3390/ijms25052667 -
Journal of Neuroinflammation Jan 2024Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by the infiltration of inflammatory cells and demyelination of nerves. Mitochondrial dysfunction... (Review)
Review
Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by the infiltration of inflammatory cells and demyelination of nerves. Mitochondrial dysfunction has been implicated in the pathogenesis of MS, as studies have shown abnormalities in mitochondrial activities, metabolism, mitochondrial DNA (mtDNA) levels, and mitochondrial morphology in immune cells of individuals with MS. The presence of mitochondrial dysfunctions in immune cells contributes to immunological dysregulation and neurodegeneration in MS. This review provided a comprehensive overview of mitochondrial dysfunction in immune cells associated with MS, focusing on the potential consequences of mitochondrial metabolic reprogramming on immune function. Current challenges and future directions in the field of immune-metabolic MS and its potential as a therapeutic target were also discussed.
Topics: Humans; Multiple Sclerosis; Mitochondria; DNA, Mitochondrial; Mitochondrial Diseases
PubMed: 38243312
DOI: 10.1186/s12974-024-03016-8 -
Journal of Translational Medicine Dec 2023Sepsis-caused multi-organ failure remains the major cause of morbidity and mortality in intensive care units with limited therapeutics. Nicotinamide mononucleotide...
BACKGROUND
Sepsis-caused multi-organ failure remains the major cause of morbidity and mortality in intensive care units with limited therapeutics. Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD), has been recently reported to be protective in sepsis; however, its therapeutic effects remain to be determined. This study sought to investigate the therapeutic effects of NMN in septic organ failure and its underlying mechanisms.
METHODS
Sepsis was induced by feces-injection-in-peritoneum in mice. NMN was given after an hour of sepsis onset. Cultured neutrophils, macrophages and endothelial cells were incubated with various agents.
RESULTS
We demonstrate that administration of NMN elevated NAD levels and reduced serum lactate levels, oxidative stress, inflammation, and caspase-3 activity in multiple organs of septic mice, which correlated with the attenuation of heart dysfunction, pulmonary microvascular permeability, liver injury, and kidney dysfunction, leading to lower mortality. The therapeutic effects of NMN were associated with lower bacterial burden in blood, and less ROS production in septic mice. NMN improved bacterial phagocytosis and bactericidal activity of macrophages and neutrophils while reducing the lipopolysaccharides-induced inflammatory response of macrophages. In cultured endothelial cells, NMN mitigated mitochondrial dysfunction, inflammation, apoptosis, and barrier dysfunction induced by septic conditions, all of which were offset by SIRT3 inhibition.
CONCLUSION
NAD repletion with NMN prevents mitochondrial dysfunction and restrains bacterial dissemination while limiting inflammatory damage through SIRT3 signaling in sepsis. Thus, NMN may represent a therapeutic option for sepsis.
Topics: Mice; Animals; NAD; Nicotinamide Mononucleotide; Sirtuin 3; Endothelial Cells; Inflammation; Mitochondrial Diseases; Sepsis
PubMed: 38057866
DOI: 10.1186/s12967-023-04767-3 -
Journal of Translational Medicine Mar 2024Mitochondria are cytoplasmic organelles having a fundamental role in the regulation of neural stem cell (NSC) fate during neural development and maintenance.During... (Review)
Review
Mitochondria are cytoplasmic organelles having a fundamental role in the regulation of neural stem cell (NSC) fate during neural development and maintenance.During embryonic and adult neurogenesis, NSCs undergo a metabolic switch from glycolytic to oxidative phosphorylation with a rise in mitochondrial DNA (mtDNA) content, changes in mitochondria shape and size, and a physiological augmentation of mitochondrial reactive oxygen species which together drive NSCs to proliferate and differentiate. Genetic and epigenetic modifications of proteins involved in cellular differentiation (Mechanistic Target of Rapamycin), proliferation (Wingless-type), and hypoxia (Mitogen-activated protein kinase)-and all connected by the common key regulatory factor Hypoxia Inducible Factor-1A-are deemed to be responsible for the metabolic shift and, consequently, NSC fate in physiological and pathological conditions.Both primary mitochondrial dysfunction due to mutations in nuclear DNA or mtDNA or secondary mitochondrial dysfunction in oxidative phosphorylation (OXPHOS) metabolism, mitochondrial dynamics, and organelle interplay pathways can contribute to the development of neurodevelopmental or progressive neurodegenerative disorders.This review analyses the physiology and pathology of neural development starting from the available in vitro and in vivo models and highlights the current knowledge concerning key mitochondrial pathways involved in this process.
Topics: Adult; Humans; Neurodegenerative Diseases; Mitochondria; DNA, Mitochondrial; Oxidative Phosphorylation; Hypoxia; Neural Stem Cells; Mitochondrial Diseases
PubMed: 38438847
DOI: 10.1186/s12967-024-05041-w -
Cell Reports Feb 2024Mitochondrial dysfunction is a hallmark of cellular senescence, with the loss of mitochondrial function identified as a potential causal factor contributing to...
Mitochondrial dysfunction is a hallmark of cellular senescence, with the loss of mitochondrial function identified as a potential causal factor contributing to senescence-associated decline in cellular functions. Our recent findings revealed that ectopic expression of the pluripotency transcription factor NANOG rejuvenates dysfunctional mitochondria of senescent cells by rewiring metabolic pathways. In this study, we report that NANOG restores the expression of key enzymes, PYCR1 and PYCR2, in the proline biosynthesis pathway. Additionally, senescent mesenchymal stem cells manifest severe mitochondrial respiratory impairment, which is alleviated through proline supplementation. Proline induces mitophagy by activating AMP-activated protein kinase α and upregulating Parkin expression, enhancing mitochondrial clearance and ultimately restoring cell metabolism. Notably, proline treatment also mitigates several aging hallmarks, including DNA damage, senescence-associated β-galactosidase, inflammatory cytokine expressions, and impaired myogenic differentiation capacity. Overall, this study highlights the role of proline in mitophagy and its potential in reversing senescence-associated mitochondrial dysfunction and aging hallmarks.
Topics: Humans; Mitochondria; Cellular Senescence; Proline; Mitochondrial Diseases
PubMed: 38354087
DOI: 10.1016/j.celrep.2024.113738 -
EMBO Reports Dec 2023Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main...
Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations is redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline-induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α-mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases.
Topics: Humans; Mitochondrial Ribosomes; Protein Serine-Threonine Kinases; Cell Survival; Tetracyclines; Endoribonucleases; Endoplasmic Reticulum Stress; Mitochondrial Diseases
PubMed: 37818824
DOI: 10.15252/embr.202357228 -
Biochemistry. Biokhimiia Dec 2023Despite the diverse manifestations of aging across different species, some common aging features and underlying mechanisms are shared. In particular, mitochondria appear... (Review)
Review
Despite the diverse manifestations of aging across different species, some common aging features and underlying mechanisms are shared. In particular, mitochondria appear to be among the most vulnerable systems in both metazoa and fungi. In this review, we discuss how mitochondrial dysfunction is related to replicative aging in the simplest eukaryotic model, the baker's yeast Saccharomyces cerevisiae. We discuss a chain of events that starts from asymmetric distribution of mitochondria between mother and daughter cells. With age, yeast mother cells start to experience a decrease in mitochondrial transmembrane potential and, consequently, a decrease in mitochondrial protein import efficiency. This induces mitochondrial protein precursors in the cytoplasm, the loss of mitochondrial DNA (mtDNA), and at the later stages - cell death. Interestingly, yeast strains without mtDNA can have either increased or decreased lifespan compared to the parental strains with mtDNA. The direction of the effect depends on their ability to activate compensatory mechanisms preventing or mitigating negative consequences of mitochondrial dysfunction. The central role of mitochondria in yeast aging and death indicates that it is one of the most complex and, therefore, deregulation-prone systems in eukaryotic cells.
Topics: Humans; Saccharomyces cerevisiae; DNA, Mitochondrial; Mitochondria; Saccharomyces cerevisiae Proteins; Mitochondrial Proteins; Mitochondrial Diseases
PubMed: 38462446
DOI: 10.1134/S0006297923120040 -
Neurotherapeutics : the Journal of the... Jan 2024This paper provides an overview of the different types of mitochondrial myopathies (MM), associated phenotypes, genotypes as well as a practical clinical approach... (Review)
Review
This paper provides an overview of the different types of mitochondrial myopathies (MM), associated phenotypes, genotypes as well as a practical clinical approach towards disease diagnosis, surveillance, and management. nDNA-related MM are more common in pediatric-onset disease whilst mtDNA-related MMs are more frequent in adults. Genotype-phenotype correlation in MM is challenging due to clinical and genetic heterogeneity. The multisystemic nature of many MMs adds to the diagnostic challenge. Diagnostic approaches utilizing genetic sequencing with next generation sequencing approaches such as gene panel, exome and genome sequencing are available. This aids molecular diagnosis, heteroplasmy detection in MM patients and furthers knowledge of known mitochondrial genes. Precise disease diagnosis can end the diagnostic odyssey for patients, avoid unnecessary testing, provide prognosis, facilitate anticipatory management, and enable access to available therapies or clinical trials. Adjunctive tests such as functional and exercise testing could aid surveillance of MM patients. Management requires a multi-disciplinary approach, systemic screening for comorbidities, cofactor supplementation, avoidance of substances that inhibit the respiratory chain and exercise training. This update of the current understanding on MMs provides practical perspectives on current diagnostic and management approaches for this complex group of disorders.
Topics: Humans; Child; Mitochondrial Myopathies; Mitochondria; High-Throughput Nucleotide Sequencing; Mitochondrial Diseases
PubMed: 38241155
DOI: 10.1016/j.neurot.2023.11.001 -
Cell Communication and Signaling : CCS Aug 2023Mesenchymal stem cells (MSCs) have emerged as a promising alternative treatment for liver disease due to their roles in regeneration, fibrosis inhibition, and... (Review)
Review
Mesenchymal stem cells (MSCs) have emerged as a promising alternative treatment for liver disease due to their roles in regeneration, fibrosis inhibition, and immunoregulation. Mitochondria are crucial in maintaining hepatocyte integrity and function. Mitochondrial dysfunction, such as impaired synthesis of adenosine triphosphate (ATP), decreased activity of respiratory chain complexes, and altered mitochondrial dynamics, is observed in most liver diseases. Accumulating evidence has substantiated that the therapeutic potential of MSCs is mediated not only through their cell replacement and paracrine effects but also through their regulation of mitochondrial dysfunction in liver disease. Here, we comprehensively review the involvement of mitochondrial dysfunction in the development of liver disease and how MSCs can target mitochondrial dysfunction. We also discuss recent advances in a novel method that modifies MSCs to enhance their functions in liver disease. A full understanding of MSC restoration of mitochondrial function and the underlying mechanisms will provide innovative strategies for clinical applications. Video Abstract.
Topics: Humans; Liver Diseases; Mitochondria; Mitochondrial Membranes; Adenosine Triphosphate; Mesenchymal Stem Cells
PubMed: 37596671
DOI: 10.1186/s12964-023-01230-0