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BACKGROUND: Information about dysarthria and dysphagia in mitochondrial diseases (MD) is scarce. However, this knowledge is needed to identify speech and swallowing problems early, to monitor the disease course, and to develop and offer optimal treatment and support. This study therefore aims to examine the prevalence and severity of dysarthria and dysphagia in patients with MD and its relation to clinical phenotype and disease severity. Secondary aim is to determine clinically relevant outcome measures for natural history studies and clinical trials. METHODS: This retrospective cross-sectional medical record study includes adults (age ≥ 18 years) diagnosed with genetically confirmed MD who participated in a multidisciplinary admission within the Radboud center for mitochondrial medicine between January 2015 and April 2023. Dysarthria and dysphagia were examined by administering the Radboud dysarthria assessment, swallowing speed, dysphagia limit, test of mastication and swallowing solids (TOMASS), and 6-min mastication test (6MMT). The disease severity was assessed using the Newcastle mitochondrial disease scale for adults (NMDAS). RESULTS: The study included 224 patients with MD with a median age of 42 years of whom 37.5% were male. The pooled prevalence of dysarthria was 33.8% and of dysphagia 35%. Patients with MD showed a negative deviation from the norm on swallowing speed, TOMASS (total time) and the 6MMT. Furthermore, a significant moderate relation was found between the presence of dysarthria and the clinical phenotypes. There was a statistically significant difference in total time on the TOMASS between the clinical phenotypes. Finally, disease severity showed a significant moderate relation with the severity of dysarthria and a significant weak relation with the severity of dysphagia. CONCLUSION: Dysarthria and dysphagia occur in about one-third of patients with MD. It is important for treating physicians to pay attention to this subject because of the influence of both disorders on social participation and wellbeing. Referral to a speech and language therapist should therefore be considered, especially in patients with a more severe clinical phenotype. The swallowing speed, TOMASS and 6MMT are the most clinically relevant tests to administer.
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Trastornos de Deglución , Disartria , Enfermedades Mitocondriales , Humanos , Trastornos de Deglución/etiología , Trastornos de Deglución/fisiopatología , Disartria/etiología , Disartria/fisiopatología , Masculino , Femenino , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/fisiopatología , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Estudios Transversales , Anciano , Índice de Severidad de la Enfermedad , Prevalencia , Deglución , Adulto Joven , FenotipoRESUMEN
Acute lung injury (ALI) is one of the life-threatening complications of sepsis, and macrophage polarization plays a crucial role in the sepsis-associated ALI. However, the regulatory mechanisms of macrophage polarization in ALI and in the development of inflammation are largely unknown. In this study, we demonstrated that macrophage polarization occurs in sepsis-associated ALI and is accompanied by mitochondrial dysfunction and inflammation, and a decrease of PRDX3 promotes the initiation of macrophage polarization and mitochondrial dysfunction. Mechanistically, PRDX3 overexpression promotes M1 macrophages to differentiate into M2 macrophages, and enhances mitochondrial functional recovery after injury by reducing the level of glycolysis and increasing TCA cycle activity. In conclusion, we identified PRDX3 as a critical hub integrating oxidative stress, inflammation, and metabolic reprogramming in macrophage polarization. The findings illustrate an adaptive mechanism underlying the link between macrophage polarization and sepsis-associated ALI.
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Lesión Pulmonar Aguda , Macrófagos , Peroxiredoxina III , Humanos , Lesión Pulmonar Aguda/metabolismo , Inflamación/metabolismo , Lipopolisacáridos , Macrófagos/metabolismo , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/metabolismo , Peroxiredoxina III/metabolismo , Sepsis/metabolismo , Animales , RatonesRESUMEN
BACKGROUND AND PURPOSE: Identifying vestibular causes of dizziness and unsteadiness in multi-sensory neurological disease can be challenging, with problems typically attributed to central or peripheral nerve involvement. Acknowledging vestibular dysfunction as part of the presentation provides an opportunity to access targeted vestibular rehabilitation, for which extensive evidence exists. A diagnostic framework was developed and validated to detect vestibular dysfunction, benign paroxysmal positional vertigo or vestibular migraine. The specificity and sensitivity of the diagnostic framework was tested in patients with primary mitochondrial disease. METHODS: Adults with a confirmed diagnosis of primary mitochondrial disease were consented, between September 2020 and February 2022. Participants with and without dizziness or unsteadiness underwent remote physiotherapy assessment and had in-person detailed neuro-otological assessment. The six framework question responses were compared against objective neuro-otological assessment or medical notes. The output was binary, with sensitivity and specificity calculated. RESULTS: Seventy-four adults completed the study: age range 20-81 years (mean 48 years, ±SD 15.05 years); ratio 2:1 female to male. The framework identified a vestibular diagnosis in 35 participants, with seven having two diagnoses. The framework was able to identify vestibular diagnoses in adults with primary mitochondrial disease, with a moderate (40-59) to very high (90-100) sensitivity and positive predictive value, and moderate to high (60-74) to very high (90-100) specificity and negative predictive value. CONCLUSIONS: Overall, the clinical framework identified common vestibular diagnoses with a moderate to very high specificity and sensitivity. This presents an opportunity for patients to access effective treatment in a timely manner, to reduce falls and improve quality of life.
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Trastornos Migrañosos , Enfermedades Mitocondriales , Enfermedades Vestibulares , Adulto , Humanos , Masculino , Femenino , Adulto Joven , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Mareo/diagnóstico , Mareo/etiología , Calidad de Vida , Vértigo/diagnóstico , Vértigo/complicaciones , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/complicaciones , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/diagnóstico , Enfermedades Vestibulares/diagnóstico , Enfermedades Vestibulares/complicaciones , Vértigo Posicional Paroxístico Benigno/complicacionesRESUMEN
BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy. METHODS: A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement. RESULTS: A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ-aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted. CONCLUSIONS: These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug-related adverse events in individuals living with PMD-related epilepsy.
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Anticonvulsivantes , Enfermedades Mitocondriales , Convulsiones , Humanos , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/terapia , Convulsiones/terapia , Convulsiones/tratamiento farmacológico , Anticonvulsivantes/uso terapéutico , Consenso , Epilepsia/terapia , Epilepsia/tratamiento farmacológico , Técnica DelphiRESUMEN
Primary mitochondrial disorders (PMDs) are known for their pleiotropic manifestations in humans, affecting almost any organ or system at any time. Hematologic manifestations, such as cytopenias and sideroblastic anemia, occur in 10% to 30% of patients with confirmed PMDs. These can be the initial presenting features or complications that develop over time. Surveillance for these manifestations allows for prompt identification and treatment. This article provides an overview of the pathophysiology underpinning the hematologic effects of mitochondrial dysfunction, discussing the 3 key roles of the mitochondria in hematopoiesis: providing energy for cell differentiation and function, synthesizing heme, and generating iron-sulfur clusters. Subsequently, the diagnosis and management of mitochondrial disorders are discussed, focusing on hematologic manifestations and the specific conditions commonly associated with them. Through this, we aimed to provide a concise point of reference for those considering a mitochondrial cause for a patient's hematologic abnormality, or for those considering a hematologic manifestation in a patient with known or suspected mitochondrial disease.
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Enfermedades Hematológicas , Enfermedades Mitocondriales , Humanos , Enfermedades Mitocondriales/complicaciones , Enfermedades Hematológicas/sangre , Enfermedades Hematológicas/complicaciones , Enfermedades Hematológicas/patología , Mitocondrias/patología , Hematopoyesis , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/terapiaRESUMEN
Polycystic ovary syndrome(PCOS) is a highly prevalent endocrine and reproductive disorder characterized by ovulatory dysfunction, hyperandrogenism(HA), and polycystic ovarian morphology(PCOM). It is often accompanied by insulin resistance(IR), obesity, and metabolic disorders and can lead to cardiovascular diseases, endometrial carcinoma and many other late complications, seriously affecting the physical and mental health and quality of life in premenopausal women. The etiology of PCOS is still unknown and many scholars assume that mitochondrial dysfunction may represent a major pathogenic factor in PCOS in recent years. With a holistic view, treatment based on syndrome differentiation, and multi-system and multi-target treatment manner, traditional Chinese medicine(TCM) can mitigate the symptoms and signs of PCOS from multiple aspects. Although there have been reviews on the mechanism of mitochondrial dysfunction in PCOS, there is still a lack of reviews on the intervention of mitochondrial function by TCM to treat PCOS. Therefore, this paper focuses on the role of mitochondrial dysfunction in PCOS and summarizes the studies about the TCM intervention of PCOS by regulating the mitochondrial function, inflammation, oxidative stress(OS), autophagy, and apoptosis in the last five years, aiming to shed new light on the prevention and treatment of PCOS with TCM.
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Medicina Tradicional China , Enfermedades Mitocondriales , Síndrome del Ovario Poliquístico , Femenino , Humanos , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/terapia , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/terapiaAsunto(s)
Bradicardia , Enfermedades Mitocondriales , Humanos , Bradicardia/diagnóstico , Bradicardia/etiología , Femenino , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/complicaciones , Embarazo , Recién Nacido , Enfermedades Fetales/diagnóstico , Enfermedades Fetales/etiología , Adulto , Ultrasonografía Prenatal , MasculinoRESUMEN
BACKGROUND: Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). However, the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear. AIM: To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders. METHODS: Liver samples were collected from 16 healthy donors (HDs) and 17 advanced HBV-ACLF patients who were eligible for liver transplantation. The mitochondrial ultrastructure, metabolic characteristics, and immune microenvironment of the liver were assessed. More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF. RESULTS: Compared with HDs, there was extensive hepatocyte necrosis, immune cell infiltration, and ductular reaction in patients with ACLF. In patients, the liver suffered severe hypoxia, as evidenced by increased expression of hypoxia-inducible factor-1α. Swollen mitochondria and cristae were observed in the liver of patients. The number, length, width, and area of mitochondria were adaptively increased in hepatocytes. Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased, while anaerobic glycolysis was enhanced in patients with HBV-ACLF. These findings suggested that, to a greater extent, hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source. Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate, which stimulates peripheral monocyte infiltration into the liver. Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68+ HLA-DR+ macrophages and elevated levels of both interleukin-1ß and transforming growth factor-ß1 in their livers. The abundance of CD206+ CD163+ macrophages and expression of interleukin-10 decreased. The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines. CONCLUSION: The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling, leading to advanced HBV-ACLF. These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.
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Insuficiencia Hepática Crónica Agudizada , Hepatitis B Crónica , Enfermedades Mitocondriales , Humanos , Virus de la Hepatitis B , Hipoxia , Enfermedades Mitocondriales/complicacionesRESUMEN
Dynamic regulation of cellular metabolism is important for maintaining homeostasis and can directly influence immune cell function and differentiation, including NK cell responses. Persistent HIV-1 infection leads to a state of chronic immune activation, NK cell subset redistribution, and progressive NK cell dysregulation. In this study, we examined the metabolic processes that characterize NK cell subsets in HIV-1 infection, including adaptive NK cell subpopulations expressing the activating receptor NKG2C, which expand during chronic infection. These adaptive NK cells exhibit an enhanced metabolic profile in HIV-1- individuals infected with human cytomegalovirus (HCMV). However, the bioenergetic advantage of adaptive CD57+NKG2C+ NK cells is diminished during chronic HIV-1 infection, where NK cells uniformly display reduced oxidative phosphorylation (OXPHOS). Defective OXPHOS was accompanied by increased mitochondrial depolarization, structural alterations, and increased DRP-1 levels promoting fission, suggesting that mitochondrial defects are restricting the metabolic plasticity of NK cell subsets in HIV-1 infection. The metabolic requirement for the NK cell response to receptor stimulation was alleviated upon IL-15 pretreatment, which enhanced mammalian target of rapamycin complex 1 (mTORC1) activity. IL-15 priming enhanced NK cell functionality to anti-CD16 stimulation in HIV-1 infection, representing an effective strategy for pharmacologically boosting NK cell responses.
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Infecciones por Citomegalovirus , Infecciones por VIH , VIH-1 , Enfermedades Mitocondriales , Humanos , Interleucina-15 , Células Asesinas Naturales , Enfermedades Mitocondriales/complicacionesRESUMEN
Hemorrhagic shock (HS) is one of the leading causes of death among young adults worldwide. Multiple organ dysfunction in HS is caused by an imbalance between tissue oxygen supply and demand, which is closely related to the poor prognosis of patient. Mitochondrial dysfunction is one of the key mechanisms contributing to multiple organ dysfunction in HS, while mitochondrial quality control regulates mitochondrial function through a series of processes, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, mitochondrial-derived vesicles, and mitochondrial protein homeostasis. Modulating mitochondrial quality control can improve organ dysfunction. This review aims to summarize the effects of mitochondrial dysfunction on organ function in HS and discuss the potential mechanisms of mitochondrial quality control, providing insights into the injury mechanisms underlying HS and guiding clinical management.
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Enfermedades Mitocondriales , Choque Hemorrágico , Adulto Joven , Humanos , Insuficiencia Multiorgánica/etiología , Choque Hemorrágico/complicaciones , Mitocondrias , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/metabolismoRESUMEN
In recent years, global warming has led to frequent instances of extremely high temperatures during summer, arousing significant concern about the adverse effects of high temperature. Among these, heat stroke is the most serious, which has detrimental effects on the all organs of human body, especially on brain. However, the comprehensive pathogenesis leading to brain damage remains unclear. In this study, we constructed a mouse model of heat stroke and conducted multi-omics profiling to identify relevant pathogenesis induced by heat stroke. The mice were placed in a constant temperature chamber at 42 °C with a humidity of 50 %, and the criteria for success in modeling were that the rectal temperature reached 42 °C and that the mice were trembling. Then the mice were immediately taken out for further experiments. Firstly, we conducted cFos protein localization and identified the cerebral cortex, especially the anterior cingulate cortex as the region exhibiting the most pronounced damage. Secondly, we performed metabolomics, transcriptomics, and proteomics analysis on cerebral cortex. This multi-omics investigation unveiled noteworthy alterations in proteins and metabolites within pathways associated with neurotransmitter systems, heatstroke-induced mitochondrial dysfunction, encompassing histidine and pentose phosphate metabolic pathways, as well as oxidative stress. In addition, the cerebral cortex exhibited pronounced Reactive Oxygen Species (ROS) production, alongside significant downregulation of the mitochondrial outer membrane protein Tomm40 and mitochondrial permeability transition pore, implicating cerebral cortex mitochondrial dysfunction as the primary instigator of neural impairment. This study marks a significant milestone as the first to employ multi-omics analysis in exploring the molecular mechanisms underlying heat stroke-induced damage in cerebral cortex neurons. It comprehensively identifies all potentially impacted pathways by heat stroke, laying a solid foundation for ensuing research endeavors. Consequently, this study introduces a fresh angle to clinical approaches in heatstroke prevention and treatment, as well as establishes an innovative groundwork for shaping future-forward environmental policies.
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Golpe de Calor , Enfermedades Mitocondriales , Ratones , Humanos , Animales , Multiómica , Encéfalo/metabolismo , Corteza Cerebral/patología , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/metabolismoRESUMEN
Septic cardiomyopathy (SCM) has a high incidence and complex pathogenesis, which can significantly increase the mortality of sepsis patients. NOD-like receptor protein 3 (NLRP3) inflammatory corpuscles play an important role in the pathogenesis of SCM. Mitochondrial dysfunction in cardiomyocytes is also one of the important pathogenesis of SCM. Activation of NLRP3 inflammatory corpuscles is closely related to mitochondrial dysfunction. The study of interaction mechanism between the two is helpful to find a new therapeutic scheme for SCM. This article reviews the interaction between NLRP3 inflammatory corpuscles and mitochondrial dysfunction in the pathogenesis of SCM, as well as the related mechanisms of traditional Chinese medicine (TCM) prevention and treatment of SCM, providing theoretical reference for further exploring therapeutic targets for SCM.
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Cardiomiopatías , Enfermedades Mitocondriales , Sepsis , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas NLR , Cardiomiopatías/etiología , Sepsis/metabolismo , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/metabolismoRESUMEN
Acute kidney injury (AKI) is a common complication of cisplatin chemotherapy, which greatly limits its clinical effect and application. This study explored the function of solute Carrier Family 31 Member 1 (SLC31A1) in cisplatin-induced AKI and its possible mechanism. Mice and HK-2 cells were exposed to cisplatin to establish the in vivo and in vitro AKI models. Cell viability was detected by CCK-8. Mitochondrial and oxidative damage was determined by Mito-Tracker Green staining, mtROS level, ATP production, mitochondrial membrane potential, MDA content and CAT activity. AKI was evaluated by renal function and histopathological changes. Apoptosis was detected by TUNEL and caspase-3 expression. Molecule expression was measured by RT-qPCR, Western blotting, and immunohistochemistry. Molecular mechanism was studied by luciferase reporter assay and ChIP. SLC31A1 level was predominantly increased by cisplatin exposure in AKI models. Notably, copper ion (Cu+) level was enhanced by cisplatin challenge. Moreover, Cu+ supplementation intensified cisplatin-induced cell death, mitochondrial dysfunction, and oxidative stress in HK-2 cells, indicating the involvement of cuproptosis in cisplatin-induced AKI, whereas these changes were partially counteracted by SLC31A1 knockdown. E74 like ETS transcription factor 3 (ELF3) could directly bind to SLC31A1 promoter and promote its transcription. ELF3 was up-regulated and positively correlated with SLC31A1 expression upon cisplatin-induced AKI. SLC31A1 silencing restored renal function, alleviated mitochondrial dysfunction, and apoptosis in cisplatin-induced AKI mice. ELF3 transcriptionally activated SLC31A1 to trigger cuproptosis that drove cisplatin-induced AKI through mitochondrial dysfunction, indicating that SLC31A1 might be a promising therapeutic target to mitigate AKI during cisplatin chemotherapy.
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Lesión Renal Aguda , Cisplatino , Cobre , Animales , Ratones , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Apoptosis , Cisplatino/efectos adversos , Cobre/metabolismo , Proteínas Transportadoras de Cobre , Enfermedades Mitocondriales/complicacionesRESUMEN
Sepsis-induced acute lung injury (ALI) is a serious condition with a high incidence. Mitochondrial dysfunction and the release of mitochondrial DNA (mtDNA) play a crucial role in the occurrence and development of sepsis-induced ALI. In sepsis, mitochondrial dysfunction causes energy depletion of cells and dysfunction of tissue cell repair mechanisms, leading to ALI. In addition, the release of mtDNA leads to a more intense inflammatory response, exacerbating sepsis-induced ALI. This article reviews the pathophysiological mechanism of mitochondrial dysfunction and mtDNA release in sepsis and the current research status, in order to provide direction for the evaluation, treatment and prevention of sepsis-induced ALI.
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Lesión Pulmonar Aguda , Enfermedades Mitocondriales , Sepsis , Humanos , ADN Mitocondrial/genética , ADN Mitocondrial/farmacología , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/prevención & control , Mitocondrias , Sepsis/complicaciones , Lipopolisacáridos/farmacología , Enfermedades Mitocondriales/complicaciones , PulmónRESUMEN
This comprehensive review delves into the pivotal role of mitochondria in doxorubicin-induced cardiotoxicity, a significant complication limiting the clinical use of this potent anthracycline chemotherapeutic agent. Doxorubicin, while effective against various malignancies, is associated with dose-dependent cardiotoxicity, potentially leading to irreversible cardiac damage. The review meticulously dissects the molecular mechanisms underpinning this cardiotoxicity, particularly focusing on mitochondrial dysfunction, a central player in this adverse effect. Central to the discussion is the concept of mitochondrial quality control, including mitochondrial dynamics (fusion/fission balance) and mitophagy. The review presents evidence linking aberrations in these processes to cardiotoxicity in doxorubicin-treated patients. It elucidates how doxorubicin disrupts mitochondrial dynamics, leading to an imbalance between mitochondrial fission and fusion, and impairs mitophagy, culminating in the accumulation of dysfunctional mitochondria and subsequent cardiac cell damage. Furthermore, the review explores emerging therapeutic strategies targeting mitochondrial dysfunction. It highlights the potential of modulating mitochondrial dynamics and enhancing mitophagy to mitigate doxorubicin-induced cardiac damage. These strategies include pharmacological interventions with mitochondrial fission inhibitors, fusion promoters, and agents that modulate mitophagy. The review underscores the promising results from preclinical studies while advocating for more extensive clinical trials to validate these approaches in human patients. In conclusion, this review offers valuable insights into the intricate relationship between mitochondrial dysfunction and doxorubicin-mediated cardiotoxicity. It underscores the need for continued research into targeted mitochondrial therapies as a means to improve the cardiac safety profile of doxorubicin, thereby enhancing the overall treatment outcomes for cancer patients.
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Cardiotoxicidad , Enfermedades Mitocondriales , Humanos , Cardiotoxicidad/etiología , Cardiotoxicidad/metabolismo , Cardiotoxicidad/patología , Doxorrubicina/efectos adversos , Mitocondrias , Antibióticos Antineoplásicos/efectos adversos , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Miocitos CardíacosRESUMEN
Mitochondria are essential for human metabolic function. Over 350 genetic mutations are associated with mitochondrial diseases, which are inherited in a matrilineal fashion. In mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), defective mitochondrial function and resultant impaired cellular energy production compromise vascular perfusion in affected tissues. Early diagnostic criteria suggested the diagnosis should be considered in those under 40. However, a broader range of phenotypes are now recognised, including those that present for the first time later in life. The primary presenting feature in MELAS is a stroke-like episode invariably resulting in patients undergoing neuroradiological imaging. We present a case of a woman with a first presentation of a stroke-like episode and seizures in her 40s who was eventually diagnosed with MELAS. We detail her clinical presentation, treatment and diagnosis, emphasising the role of serial imaging in her diagnosis.
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Acidosis Láctica , Síndrome MELAS , Enfermedades Mitocondriales , Encefalomiopatías Mitocondriales , Accidente Cerebrovascular , Femenino , Humanos , Síndrome MELAS/diagnóstico , Síndrome MELAS/diagnóstico por imagen , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/complicaciones , Enfermedades Mitocondriales/complicacionesRESUMEN
Hyperkinesias in a patient with complex-I deficiency due to the variant m.10191T>C in MT-ND3 have not been previously reported. The patient is a 32 years-old female with multisystem mitochondrial disease due to variant m.10191T>C in MT-ND3, who has been experiencing episodic, spontaneous or induced abnormal movements since age 23. The abnormal movements started as right hemi-athetosis, bilateral dystonia of the legs, or unilateral dystonia of the right arm and leg. They often progressed to severe ballism, involving the trunk, and limbs. The arms were more dystonic than the legs. In conclusion, complex-I deficiency due to the variant m.10191T>C in MT-ND3 may manifest as multisystem disease including hyperkinesias. Neurologists should be aware of hyperkinesias as a manifestation of complex-I deficiency.
RésuméL'hyperkinésie d'une patiente atteinte d'un déficit en complexe I dû à la variante m.10191T>C du gène MT-ND3 n'a jamais été rapportée auparavant. La patiente est une femme de 32 ans atteinte d'une maladie mitochondriale multisystémique due à la variante m.10191T>C du gène MT-ND3, qui présente des mouvements anormaux épisodiques, spontanés ou provoqués depuis l'âge de 18 ans. mouvements anormaux épisodiques, spontanés ou provoqués depuis l'âge de 23 ans. Les mouvements anormaux ont commencé par une hémiathétose droite, dystonie bilatérale des jambes ou dystonie unilatérale du bras et de la jambe droite. Ils ont souvent évolué vers un ballisme sévère, impliquant le tronc et les membres. le tronc et les membres. Les bras étaient plus dystoniques que les jambes. En conclusion, le déficit en complexe I dû à la variante m.10191T>C du gène MT-ND3 peut se manifester par une maladie multisystémique comprenant des hyperkinésies. Les neurologues doivent être conscients que l'hyperkinésie est une manifestation du déficit en complexe-I. de la déficience en complexe I.
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Enfermedad de Leigh , Humanos , Femenino , Adulto , Enfermedad de Leigh/complicaciones , Enfermedad de Leigh/diagnóstico , Hipercinesia/etiología , Complejo I de Transporte de Electrón/deficiencia , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , MutaciónRESUMEN
BACKGROUND: Sepsis-induced acute lung injury (ALI) is one of the serious life-threatening complications of sepsis and is pathologically associated with mitochondrial dysfunction. Ginsenoside Rg1 has good therapeutic effects on ALI. Herein, the pharmacological effects of Rg1 in sepsis-induced ALI were investigated. METHODS: Sepsis-induced ALI models were established by CLP operation and LPS treatment. HE staining was adopted to analyze lung pathological changes. The expression and secretion of cytokines were measured by RT-qPCR and ELISA. Cell viability and apoptosis were assessed by MTT assay, flow cytometry and TUNEL staining. ROS level and mitochondrial membrane potential (MMP) were analyzed using DHE probe and JC-1 staining, respectively. FBXO3 m6A level was assessed using MeRIP assay. The interactions between FBXO3, YTHDF1, and PGC-1α were analyzed by Co-IP or RIP. RESULTS: Rg1 administration ameliorated LPS-induced epithelial cell inflammation, apoptosis, and mitochondrial dysfunction in a dose-dependent manner. Mechanically, Rg1 reduced PGC-1α ubiquitination modification level by inhibiting FBXO3 expression m6A-YTHDF1 dependently. As expected, Rg1's mitigative effect on LPS-induced inflammation, apoptosis and mitochondrial dysfunction in lung epithelial cells was abolished by FBXO3 overexpression. Moreover, FBXO3 upregulation eliminated the restoring effect of Rg1 on CLP-induced lung injury in rats. CONCLUSION: Rg1 activated PGC-1α/Nrf2 signaling pathway by reducing FBXO3 stability in an m6A-YTHDF1-dependent manner to improve mitochondrial function in lung epithelial cells during sepsis-induced ALI progression.
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Lesión Pulmonar Aguda , Ginsenósidos , Enfermedades Mitocondriales , Sepsis , Ratas , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Lipopolisacáridos/farmacología , Lipopolisacáridos/uso terapéutico , Transducción de Señal , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/complicaciones , Inflamación , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Enfermedades Mitocondriales/complicacionesRESUMEN
We aimed to provide a detailed phenotypic description of status epilepticus (SE) in a large cohort of patients with POLG disease and identify prognostic biomarkers to improve the management of this life-threatening condition. In a multinational, retrospective study with data on patients with POLG disease from seven European countries, we identified those who had SE. The age of SE onset, accompanying clinical, laboratory, imaging and genetic findings were analysed. One hundred and ninety-five patients with genetically confirmed POLG disease were recruited, of whom 67% (130/194) had epilepsy. SE was identified in 77% (97/126), with a median age of SE onset of 7 years. SE was the presenting symptom of the disease in 43% (40/93) of those with SE, while 57% (53/93) developed SE during the disease course. Convulsive SE was reported in 97% (91/94) followed by epilepsia partialis continua in 67% (56/84). Liver impairment 78% (74/95), ataxia 69% (60/87), stroke-like episodes 57% (50/88), were the major comorbidities. In the majority (66%; 57/86) with SE this became refractory or super-refractory. The presence of seizures was associated with significantly higher mortality compared to those without (P ≤ 0.001). The median time from SE debut to death was 5 months. SE is a major clinical feature of POLG disease in early and juvenile to adult-onset disease and can be the presenting feature or arise as part of a multisystem disease. It is associated with high morbidity and mortality, with the majority of patients with SE going on to develop refractory or super-refractory SE.