scholarly journals Epilepsy in Mitochondrial Diseases—Current State of Knowledge on Aetiology and Treatment

Children ◽  
2021 ◽  
Vol 8 (7) ◽  
pp. 532
Author(s):  
Dorota Wesół-Kucharska ◽  
Dariusz Rokicki ◽  
Aleksandra Jezela-Stanek
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Clinical Picture ◽  
Poor Prognosis ◽  
Treatment Options ◽  
Mitochondrial Diseases ◽  
Energy Deficit ◽  
Atp Production ◽  
Current State

Mitochondrial diseases are a heterogeneous group of diseases resulting from energy deficit and reduced adenosine triphosphate (ATP) production due to impaired oxidative phosphorylation. The manifestation of mitochondrial disease is usually multi-organ. Epilepsy is one of the most common manifestations of diseases resulting from mitochondrial dysfunction, especially in children. The onset of epilepsy is associated with poor prognosis, while its treatment is very challenging, which further adversely affects the course of these disorders. Fortunately, our knowledge of mitochondrial diseases is still growing, which gives hope for patients to improve their condition in the future. The paper presents the pathophysiology, clinical picture and treatment options for epilepsy in patients with mitochondrial disease.

scholarly journals Imaging mass cytometry reveals generalised deficiency in OXPHOS complexes in Parkinson’s disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Chun Chen ◽  
David McDonald ◽  
Alasdair Blain ◽  
Ashwin Sachdeva ◽  
Laura Bone ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Dopaminergic Neurons ◽  
Neuronal Response ◽  
Proteomic Profiling ◽  
Mass Cytometry ◽  
And Control

AbstractHere we report the application of a mass spectrometry-based technology, imaging mass cytometry, to perform in-depth proteomic profiling of mitochondrial complexes in single neurons, using metal-conjugated antibodies to label post-mortem human midbrain sections. Mitochondrial dysfunction, particularly deficiency in complex I has previously been associated with the degeneration of dopaminergic neurons in Parkinson’s disease. To further our understanding of the nature of this dysfunction, and to identify Parkinson’s disease specific changes, we validated a panel of antibodies targeting subunits of all five mitochondrial oxidative phosphorylation complexes in dopaminergic neurons from Parkinson’s disease, mitochondrial disease, and control cases. Detailed analysis of the expression profile of these proteins, highlighted heterogeneity between individuals. There is a widespread decrease in expression of all complexes in Parkinson’s neurons, although more severe in mitochondrial disease neurons, however, the combination of affected complexes varies between the two groups. We also provide evidence of a potential neuronal response to mitochondrial dysfunction through a compensatory increase in mitochondrial mass. This study highlights the use of imaging mass cytometry in the assessment and analysis of expression of oxidative phosphorylation proteins, revealing the complexity of deficiencies of these proteins within individual neurons which may contribute to and drive neurodegeneration in Parkinson’s disease.

scholarly journals Mitochondrial Dysfunction in Atrial Fibrillation—Mechanisms and Pharmacological Interventions

2021 ◽  
Vol 10 (11) ◽  
pp. 2385
Author(s):  
Paweł Muszyński ◽  
Tomasz A. Bonda
Keyword(s):  
Atrial Fibrillation ◽  
Mitochondrial Dysfunction ◽  
Treatment Options ◽  
Therapeutic Interventions ◽  
Energy Deficit ◽  
Functional Changes ◽  
Electrical Instability ◽  
Ionic Fluxes ◽  
Prevention Methods ◽  
Invasive Techniques

Despite the enormous progress in the treatment of atrial fibrillation, mainly with the use of invasive techniques, many questions remain unanswered regarding the pathomechanism of the arrhythmia and its prevention methods. The development of atrial fibrillation requires functional changes in the myocardium that result from disturbed ionic fluxes and altered electrophysiology of the cardiomyocyte. Electrical instability and electrical remodeling underlying the arrhythmia may result from a cellular energy deficit and oxidative stress, which are caused by mitochondrial dysfunction. The significance of mitochondrial dysfunction in the pathogenesis of atrial fibrillation remains not fully elucidated; however, it is emphasized by the reduction of atrial fibrillation burden after therapeutic interventions improving the mitochondrial welfare. This review summarizes the mechanisms of mitochondrial dysfunction related to atrial fibrillation and current pharmacological treatment options targeting mitochondria to prevent or improve the outcome of atrial fibrillation.

scholarly journals Impaired Mitochondrial Fusion and Oxidative Phosphorylation Triggered by High Glucose Is Mediated by Tom22 in Endothelial Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-23 ◽  
Author(s):  
Yi Zeng ◽  
Qi Pan ◽  
Xiaoxia Wang ◽  
Dongxiao Li ◽  
Yajun Lin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
High Glucose ◽  
Mitochondrial Dynamics ◽  
Umbilical Vein ◽  
Vascular Complications ◽  
Mitochondrial Fusion ◽  
Mitochondrial Outer Membrane ◽  
Atp Production

Much evidence demonstrates that mitochondrial dysfunction plays a crucial role in the pathogenesis of vascular complications of diabetes. However, the signaling pathways through which hyperglycemia leads to mitochondrial dysfunction of endothelial cells are not fully understood. Here, we treated human umbilical vein endothelial cells (HUVECs) with high glucose and examined the role of translocase of mitochondrial outer membrane (Tom) 22 on mitochondrial dynamics and cellular function. Impaired Tom22 expression and protein expression of oxidative phosphorylation (OXPHOS) as well as decreased mitochondrial fusion were observed in HUVECs treated with high glucose. The deletion of Tom22 resulted in reduced mitochondrial fusion and ATP production and increased apoptosis in HUVECs. The overexpression of Tom22 restored the balance of mitochondrial dynamics and OXPHOS disrupted by high glucose. Importantly, we found that Tom22 modulates mitochondrial dynamics and OXPHOS by interacting with mitofusin (Mfn) 1. Taken together, our findings demonstrate for the first time that Tom22 is a novel regulator of both mitochondrial dynamics and bioenergetic function and contributes to cell survival following high-glucose exposure.

scholarly journals The Role of Mitonuclear Incompatibility in Bipolar Disorder Susceptibility and Resilience Against Environmental Stressors

2021 ◽  
Vol 12 ◽  
Author(s):  
Suzanne Gonzalez
Keyword(s):  
Bipolar Disorder ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Brain Function ◽  
Electron Flow ◽  
Mitochondrial Genes ◽  
Environmental Stressors ◽  
Atp Production ◽  
Co Morbidity

It has been postulated that mitochondrial dysfunction has a significant role in the underlying pathophysiology of bipolar disorder (BD). Mitochondrial functioning plays an important role in regulating synaptic transmission, brain function, and cognition. Neuronal activity is energy dependent and neurons are particularly sensitive to changes in bioenergetic fluctuations, suggesting that mitochondria regulate fundamental aspects of brain function. Vigorous evidence supports the role of mitochondrial dysfunction in the etiology of BD, including dysregulated oxidative phosphorylation, general decrease of energy, altered brain bioenergetics, co-morbidity with mitochondrial disorders, and association with genetic variants in mitochondrial DNA (mtDNA) or nuclear-encoded mitochondrial genes. Despite these advances, the underlying etiology of mitochondrial dysfunction in BD is unclear. A plausible evolutionary explanation is that mitochondrial-nuclear (mitonuclear) incompatibility leads to a desynchronization of machinery required for efficient electron transport and cellular energy production. Approximately 1,200 genes, encoded from both nuclear and mitochondrial genomes, are essential for mitochondrial function. Studies suggest that mitochondrial and nuclear genomes co-evolve, and the coordinated expression of these interacting gene products are essential for optimal organism function. Incompatibilities between mtDNA and nuclear-encoded mitochondrial genes results in inefficiency in electron flow down the respiratory chain, differential oxidative phosphorylation efficiency, increased release of free radicals, altered intracellular Ca2+ signaling, and reduction of catalytic sites and ATP production. This review explores the role of mitonuclear incompatibility in BD susceptibility and resilience against environmental stressors.

scholarly journals Generation of somatic mitochondrial DNA-replaced cells for mitochondrial dysfunction treatment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hideki Maeda ◽  
Daisuke Kami ◽  
Ryotaro Maeda ◽  
Akira Shikuma ◽  
Satoshi Gojo
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Respiratory Function ◽  
Disease Patient ◽  
Mitochondrial Diseases ◽  
Wild Type ◽  
Mutant Genotype ◽  
Isolated Mitochondria ◽  
Wide Range

AbstractMitochondrial diseases currently have no cure regardless of whether the cause is a nuclear or mitochondrial genome mutation. Mitochondrial dysfunction notably affects a wide range of disorders in aged individuals, including neurodegenerative diseases, cancers, and even senescence. Here, we present a procedure to generate mitochondrial DNA-replaced somatic cells with a combination of a temporal reduction in endogenous mitochondrial DNA and coincubation with exogeneous isolated mitochondria. Heteroplasmy in mitochondrial disease patient-derived fibroblasts in which the mutant genotype was dominant over the wild-type genotype was reversed. Mitochondrial disease patient-derived fibroblasts regained respiratory function and showed lifespan extension. Mitochondrial membranous components were utilized as a vehicle to deliver the genetic materials into endogenous mitochondria-like horizontal genetic transfer in prokaryotes. Mitochondrial DNA-replaced cells could be a resource for transplantation to treat maternal inherited mitochondrial diseases.

scholarly journals Generation of Somatic Mitochondrial DNA-Replaced Cells for Mitochondrial Dysfunction Treatment

2020 ◽  
Author(s):  
Hideki Maeda ◽  
Daisuke Kami ◽  
Ryotaro Maeda ◽  
Akira Shikuma ◽  
Satoshi Gojo
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Pluripotent Stem Cells ◽  
Disease Patient ◽  
Mitochondrial Diseases ◽  
Wild Type ◽  
Mutant Genotype ◽  
Wide Range

AbstractMitochondrial diseases currently have no cure regardless of whether the cause is a nuclear or mitochondrial genome mutation. Mitochondrial dysfunction notably affects a wide range of disorders in aged individuals, including neurodegenerative diseases, cancers, and even senescence. Here, we present a procedure to generate mitochondrial DNA-replaced somatic cells with a combination of a temporal reduction in endogenous mitochondrial DNA and coincubation with exogeneous isolated mitochondria. Heteroplasmy in mitochondrial disease patient-derived fibroblasts in which the mutant genotype was dominant over the wild-type genotype was reversed over the long term, even inducing the production of pluripotent stem cells from the mitochondrial DNA-replaced cells to maintain the genotype without a reversion to the original. Both mitochondrial disease patient-derived and aged fibroblasts could regain respiratory function and showed lifespan extension. Mitochondrial membranous components were utilized as a vehicle to deliver the genetic materials into endogenous mitochondria-like horizontal genetic transfer in prokaryotes. The mitochondrial DNA-replaced cells could be a resource for transplantation to treat not only mitochondrial diseases, but also senescence-related diseases.

SECONDARY MITOCHONDRIAL DYSFUNCTION

2021 ◽  
pp. 14-19
Author(s):  
KANIKA KHAJURIA ◽  
VIJAY KHAJURIA ◽  
VINEETA SAWHNEY
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Deoxyribonucleic Acid ◽  
Muscular Atrophy ◽  
Oxygen Species ◽  
Mt Dna ◽  
Atp Production ◽  
Vital Functions ◽  
Nuclear Deoxyribonucleic Acid

Mitochondria are the most vital organelle in the cell because of its multitask properties. They are well known for the production of energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS), which involves multiple complexes and cofactors. Mitochondria in addition to ATP production, also perform other vital functions like generation of reactive oxygen species (ROS), antioxidants, apoptosis, signaling and hormone actions. Because of their multiple actions, it is quite expected that their dysfunction will result in the number of effects. Since most vital organs exclusively depend on ATP to perform their functions, therefore impediment in its supply resulting from mitochondrial dysfunction will be detrimental and have a widespread spectrum. Neurodegenerative disorders, Huntington’s disease, cardiovascular disease (CVD), epilepsy, aging, metabolic syndrome, diabetes, autism, muscular atrophy, lou gehrig’s disease, neoplasia, down syndrome are few instances where mitochondrial dysfunction is the basic cause in pathogenesis. Mitochondrial disorders are either Primary or secondary disorders. Primary mitochondrial disease or disorder (PMD) has mitochondrial or nuclear deoxyribonucleic acid (mt DNA or nDNA) mutation affecting oxidative phosphorylation (OXPHOS). While Secondary mitochondrial dysfunction (SMD) does not involve OXPHOS but is the result of mutations in non OXPHOS genes. Secondary mitochondrial dysfunction (SMD) can also be acquired secondary to adverse factors those cause oxidative stress. All this highlights the role of mitochondria and makes it a new therapeutic target in managing these disorders. The present review has briefly discussed the secondary mitochondrial dysfunctional disorders and the approach to tackle it.

scholarly journals Mitochondrial transcription and translation: overview

2018 ◽  
Vol 62 (3) ◽  
pp. 309-320 ◽  
Author(s):  
Aaron R. D’Souza ◽  
Michal Minczuk
Keyword(s):  
Gene Expression ◽  
Mitochondrial Genome ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Diseases ◽  
Mitochondrial Transcription ◽  
Inner Membrane ◽  
Atp Production

Mitochondria are the major source of ATP in the cell. Five multi-subunit complexes in the inner membrane of the organelle are involved in the oxidative phosphorylation required for ATP production. Thirteen subunits of these complexes are encoded by the mitochondrial genome often referred to as mtDNA. For this reason, the expression of mtDNA is vital for the assembly and functioning of the oxidative phosphorylation complexes. Defects of the mechanisms regulating mtDNA gene expression have been associated with deficiencies in assembly of these complexes, resulting in mitochondrial diseases. Recently, numerous factors involved in these processes have been identified and characterized leading to a deeper understanding of the mechanisms that underlie mitochondrial diseases.

scholarly journals MITOCHONDRIAL DISEASE THERAPY

2021 ◽  
pp. 24-30
Author(s):  
KANIKA KHAJURIA ◽  
VIJAY KHAJURIA ◽  
VINEETA SAWHNEY
Keyword(s):  
Mitochondrial Dysfunction ◽  
Nuclear Dna ◽  
Mitochondrial Diseases ◽  
Atp Synthesis ◽  
Atp Production ◽  
Complex Disorders ◽  
Disease Therapy ◽  
Biogenesis Of Mitochondria ◽  
Beneficial Outcome

Mitochondria perform number of important functions, including synthesis of adenosine triphosphate (ATP) and generation of reactive oxygen species (ROS). Most of the organs depend on ATP to perform. Therefore, in depleted or dysfunctional mitochondrial states, there is less energy production coupled with the accumulation of oxidants. Oxidative stress is involved in the pathophysiology of various disorders especially involving neurons and the cardiovascular system. Mitochondrial diseases are a clinically heterogeneous group of disorders resulting from either inherited or spontaneous mutations in mitochondrial deoxyribonucleic acid (mtDNA) or nuclear DNA. In primary mitochondrial dysfunction disease, the mutation affects the oxidative phosphorylation (OXPHOS) functioning, while secondary mitochondrial dysfunction does not involve OXPHOS genes. Since mutations of genes are involved, therefore, therefore the mitochondrial dysfunctional states are not easy to treat. However, number of strategies that lead to increase ATP production, counter ROS facilitates improvement. The current strategy is to focus on stimulating the biogenesis of mitochondria, antioxidants, and cofactors to enhance ATP synthesis. The role of non-pharmaceuticals cannot be underestimated either. The exercise, diet, and environment influence have well-established beneficial outcome in these disorders. Gene therapy holds promise in the future management of these complex disorders.

scholarly journals Over Expression of NOS2 in Ragged-red Fibers from Patients with Mitochondrial Disorders due to Mutations in mtDNA

2018 ◽  
Vol 1 (1) ◽  
pp. 07-13
Author(s):  
Valeria Guglielmi ◽  
Matteo Marini ◽  
Giuliano Tomelleri ◽  
Gaetano Vattemi
Keyword(s):  
Nitric Oxide ◽  
Oxidative Phosphorylation ◽  
Subcellular Localization ◽  
Mitochondrial Diseases ◽  
Mitochondrial Respiratory Chain ◽  
Atp Production ◽  
Over Expression ◽  
Ragged Red Fibers ◽  
Muscle Biopsies ◽  
Inducible Nos

Mitochondrial diseases (MDs) are a group of heterogeneous disorders due to impaired oxidative phosphorylation causing defective ATP production. The histopathological hallmark is the presence ofragged-red fibers (RRFs), muscle fibers with excessive mitochondrial proliferation. Nitric oxide synthases (NOSs) are enzymes responsible of the synthesis of nitric oxide (NO), a ubiquitous signaling molecule involved in many physio-pathological processes. Three NOS isoenzymes have been identified so far including neuronal NOS (NOS1), inducible NOS (NOS2) and endothelial NOS (NOS3). Despite the expression and the subcellular localization of NOS1 and NOS3 have been previously investigated, a possible involvement of NOS2 in MDs has never been assessed. We evaluated the expression of NOS2 in muscle biopsies from 17 patients with mitochondrial respiratory chain dysfunction. Our data demonstrate that NOS2 is overexpressed in RRFs and the correspondence between NOS2 immunoreactivity and SDH staining suggests that the protein localizes to the mitochondria. Together with previous studies from the literature, these findings indicate a possible role NOSs in the pathogenic events leading to MDs

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