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European Journal of Clinical... Jul 2024Primary mitochondrial diseases (PMDs) are rare genetic disorders resulting from mutations in genes crucial for effective oxidative phosphorylation (OXPHOS) that can... (Review)
Review
OBJECTIVES AND SCOPE
Primary mitochondrial diseases (PMDs) are rare genetic disorders resulting from mutations in genes crucial for effective oxidative phosphorylation (OXPHOS) that can affect mitochondrial function. In this review, we examine the bioenergetic alterations and oxidative stress observed in cellular models of primary mitochondrial diseases (PMDs), shedding light on the intricate complexity between mitochondrial dysfunction and cellular pathology. We explore the diverse cellular models utilized to study PMDs, including patient-derived fibroblasts, induced pluripotent stem cells (iPSCs) and cybrids. Moreover, we also emphasize the connection between oxidative stress and neuroinflammation.
INSIGHTS
The central nervous system (CNS) is particularly vulnerable to mitochondrial dysfunction due to its dependence on aerobic metabolism and the correct functioning of OXPHOS. Similar to other neurodegenerative diseases affecting the CNS, individuals with PMDs exhibit several neuroinflammatory hallmarks alongside neurodegeneration, a pattern also extensively observed in mouse models of mitochondrial diseases. Based on histopathological analysis of postmortem human brain tissue and findings in mouse models of PMDs, we posit that neuroinflammation is not merely a consequence of neurodegeneration but a potential pathogenic mechanism for disease progression that deserves further investigation. This recognition may pave the way for novel therapeutic strategies for this group of devastating diseases that currently lack effective treatments.
SUMMARY
In summary, this review provides a comprehensive overview of bioenergetic alterations and redox imbalance in cellular models of PMDs while underscoring the significance of neuroinflammation as a potential driver in disease progression.
Topics: Humans; Oxidative Stress; Mitochondrial Diseases; Neuroinflammatory Diseases; Animals; Energy Metabolism; Oxidative Phosphorylation; Mice; Mitochondria; Fibroblasts; Induced Pluripotent Stem Cells; Leigh Disease; MELAS Syndrome; Disease Models, Animal
PubMed: 38644687
DOI: 10.1111/eci.14217 -
European Heart Journal. Case Reports Sep 2023Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder caused by mutations in mitochondrial DNA,...
BACKGROUND
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder caused by mutations in mitochondrial DNA, resulting in impaired energy production and affecting multiple organs. We present a suspected MELAS syndrome case with the initial symptom of chest tightness.
CASE SUMMARY
A 46-year-old man sought medical attention due to progressively worsening chest tightness during physical activity. He had been receiving treatment for type 2 diabetes for 15 years. One year ago, he presented with symptoms of hearing impairment. Transthoracic echocardiography revealed increased thickness of the left ventricular wall. Serum protein electrophoresis showed no evidence of light-chain amyloidosis, and the 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scan showed no definite uptake in the heart muscle. The patient's head magnetic resonance imaging (MRI) indicated lacunar infarcts. The lactate threshold test was positive. The biopsy of the skeletal muscle showed broken red fibre infiltration on modified Gomori trichrome staining, and electron microscopy revealed signs of mitochondrial cardiomyopathy, including mild mitochondrial swelling, lipid accumulation, and myofibril damage. A whole-exome genetic test was used to detect the m.3243A>G mutation in the MT-TL1 gene. Based on these findings, MELAS syndrome was the most probable diagnosis.
DISCUSSION
The patient presented with chest tightness in adulthood, without any accompanying psychoneurological symptoms. However, the patient presented with other symptoms, including diabetes mellitus, hearing loss, abnormal lactate levels, ischaemic lesions on head MRI, and left ventricular hypertrophy. By identifying a mutation in the MT-TL1 gene and conducting a muscle biopsy, the diagnosis of MELAS syndrome was definitively confirmed.
PubMed: 37767231
DOI: 10.1093/ehjcr/ytad441 -
European Archives of... Jun 2024Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial disease that affects various systems in the body,...
BACKGROUND
Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial disease that affects various systems in the body, particularly the brain, nervous system, and muscles. Among these systems, sensorineural hearing loss is a common additional symptom.
METHODS
A 42-year-old female patient with MELAS who experienced bilateral profound deafness and underwent bilateral sequential cochlear implantation (CIs). Speech recognition and subjective outcomes were evaluated.
RESULTS
Following the first CI follow-up, the patient exhibited improved speech recognition ability and decided to undergo the implantation of the second ear just two months after the initial CI surgery. The second CI also demonstrated enhanced speech recognition ability. Subjective outcomes were satisfactory for bilateral CIs.
CONCLUSIONS
MELAS patients receiving bilateral CIs can attain satisfactory post-CI speech recognition, spatial hearing, and sound qualities.
Topics: Humans; Female; Adult; MELAS Syndrome; Cochlear Implantation; Cochlear Implants; Hearing Loss, Sensorineural; Speech Perception
PubMed: 38409582
DOI: 10.1007/s00405-024-08532-0 -
Cureus Oct 2023Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a complex and infrequently encountered mitochondrial cytopathy. Patients...
Anesthetic Management of a Patient With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes Syndrome During Extensive Spinal Surgery With Both Motor Evoked Potentials and Somatosensory Evoked Potentials: A Case Report.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a complex and infrequently encountered mitochondrial cytopathy. Patients with MELAS often present with multi-systemic manifestations, making their anesthetic management particularly challenging. In this case report, we describe in detail our anesthetic approach for a 19-year-old male with confirmed MELAS linked to an m.3243A>G mutation. The patient had been diagnosed with MELAS at age 12 following a stroke-like episode and presented with progressive spinal deformities. He exhibited a 70° thoracic spine curvature and an 80° kyphosis, requiring a T1-L2 posterior spinal fusion. The surgical plan included neuromonitoring with both somatosensory and motor evoked potentials. Intravenous anesthetics such as propofol are typically preferred in this context due to their reduced interference with neuromonitoring compared to volatile anesthetics. Anticipating a surgical duration of six to seven hours, however, we hesitated to rely on propofol for this extended period due to its potential risks of lactic acidosis in the context of MELAS. Given that propofol infusion for extended periods (>48 hours) or at high doses (≥5 mg·kg·hour) is known to induce propofol-related infusion syndrome, and coupled with our concerns about the risk of lactic acidosis in this patient, we were compelled to design an anesthetic plan that avoided propofol altogether without excessive use of volatile anesthetics. This proactive approach ensured the maintenance of consistent neuromonitoring signals and the patient's safety, especially given his underlying mitochondrial dysfunction. Our primary rationale in presenting this case report is to highlight the challenges posed by MELAS in the setting of extended surgery, with a focus on anesthetic considerations during neuromonitoring. For prolonged surgeries that typically rely heavily on intravenous anesthetics, which interfere less with neuromonitoring than volatile anesthetics, the use of propofol should be approached with caution in MELAS contexts due to its associated risk of lactic acidosis. To our knowledge, this is the first case report that described the anesthetic management of a patient with MELAS undergoing a procedure of such duration, requiring both somatosensory and motor evoked potential neuromonitoring. We believe our experiences will serve as a reference for anesthesiologists and perioperative teams faced with similar challenging clinical situations.
PubMed: 37854475
DOI: 10.7759/cureus.47198 -
Frontiers in Neurology 2023Patients with mitochondrial disorders always show neurological deficits. However, the diversity of clinical manifestations, genetic heterogeneity and threshold effect...
INTRODUCTION
Patients with mitochondrial disorders always show neurological deficits. However, the diversity of clinical manifestations, genetic heterogeneity and threshold effect caused by maternal heredity make its diagnosis very challenging.
CASE PRESENTATION
A 30-year-old female presented to our neurology department with a recurrence of symmetrical weakness proximally in the lower extremities. Seven years ago, the patient had a sudden onset of persistent weakness in bilateral proximal lower extremities, along with elevated creatinine kinase (CK) and CK-MB. Given the diagnosis of Guillain-Barre syndrome, she was treated with high-dose glucocorticoid (GC) therapy at the local hospital and recovered. After admission to our hospital, laboratory analysis revealed elevated CK and alpha-hydroxybutyrate dehydrogenase in serum. Electrocardiography showed sinus tachycardia and left high ventricular voltage. Electromyography (EMG) and evoked potential (EP) suggested peripheral neurogenic damage of the upper and lower extremities with myogenic wear. Chronic inflammatory demyelinating polyneuropathy (CIDP) was initially considered, but neurological symptoms were not significantly improved with glucocorticoid shock therapy. An elevated level of lactate was found. The short-tau inversion recovery (STIR) axial magnetic resonance image (MRI) revealed mild hyperintensities, indicating muscle edema. Meanwhile, muscle biopsies suggested pathological changes in mitochondrial disorders (MIDs) and neuronal damage. Further mitochondrial genome analysis revealed a heteroplasmic m3271 T>C mutation in the mitochondrial tRNA-Leu gene (UUR). Collectively, the patient was finally diagnosed with mitochondrial disorder and apparently improved after the corresponding treatment to regulate energy metabolism.
CONCLUSIONS
To our knowledge, it's the first report about MELAS with 3271 mutation that have only shown peripheral nerve motion impairment. Proximal weakness is also common in CIDP. In the context of this patient's experience, mitochondrial genome analysis provides an auxiliary criterion for differential diagnosis between MIDs and CIDP. In the meantime, we discussed the clinical effect of GCs on MIDs.
PubMed: 37576015
DOI: 10.3389/fneur.2023.1179992 -
FASEB Journal : Official Publication of... Jun 2024Mitochondrial disease is a devastating genetic disorder, with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and m.3243A>G...
Mitochondrial disease is a devastating genetic disorder, with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and m.3243A>G being the most common phenotype and genotype, respectively. The treatment for MELAS patients is still less effective. Here, we performed transcriptomic and proteomic analysis in muscle tissue of MELAS patients, and discovered that the expression of molecules involved in serine catabolism were significantly upregulated, and serine hydroxymethyltransferase 2 (SHMT2) increased significantly in both the mRNA and protein levels. The SHMT2 protein level was also increased in myoblasts with m.3243A>G mutation, which was transdifferentiated from patients derived fibroblasts, accompanying with the decreased nicotinamide adenine dinucleotide (NAD)/reduced NAD (NADH) ratio and cell viability. After treating with SHMT2 inhibitor (SHIN1), the NAD/NADH ratio and cell viability in MELAS myoblasts increased significantly. Taken together, our study indicates that enhanced serine catabolism plays an important role in the pathogenesis of MELAS and that SHIN1 can be a potential small molecule for the treatment of this disease.
Topics: Humans; MELAS Syndrome; Glycine Hydroxymethyltransferase; Serine; Myoblasts; NAD; Male; Proteomics; Female; Transcriptome; Multiomics
PubMed: 38865203
DOI: 10.1096/fj.202302286RRR -
Journal of the Formosan Medical... Oct 2023The mitochondrial DNA m.3243A>G mutation can affect mitochondrial function and lead to a wide phenotypic spectrum, including mitochondrial encephalopathy with lactic...
BACKGROUND
The mitochondrial DNA m.3243A>G mutation can affect mitochondrial function and lead to a wide phenotypic spectrum, including mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, diabetes mellitus, hearing impairment, cardiac involvement, epilepsy, migraine, myopathy, and cerebellar ataxia. However, m.3243A>G has been rarely reported in patients with cerebellar ataxia as their predominant manifestation. The aim of this study is to investigate the prevalence and clinical features of m.3243A>G in a Taiwanese cohort of cerebellar ataxia with unknown genetic diagnosis.
METHODS
This retrospective cohort study conducted the mutation analysis of m.3243A>G by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) in 232 unrelated Han Chinese patients with genetically-undetermined cerebellar ataxia. The clinical presentation and neuroimaging features of patients with m.3243A>G mutation-related cerebellar ataxia were characterized.
RESULTS
We identified two patients harboring m.3243A>G mutation. These patients have suffered from apparently sporadic and slowly progressive cerebellar ataxia since age 52 and 35 years, respectively. Both patients had diabetes mellitus and/or hearing impairment. The neuroimaging studies revealed generalized brain atrophy with predominantly cerebellar involvement in both individuals and bilateral basal ganglia calcifications in one of the patients.
CONCLUSION
Mitochondrial m.3243A>G mutation accounted for 0.9% (2/232) of genetically-undetermined cerebellar ataxia in the Han Chinese cohort in Taiwan. These findings highlight the importance of investigating m.3243A>G in patients with genetically-undetermined cerebellar ataxia.
Topics: Humans; Retrospective Studies; Cerebellar Ataxia; Mutation; DNA, Mitochondrial; Diabetes Mellitus; Hearing Loss
PubMed: 37311680
DOI: 10.1016/j.jfma.2023.05.031 -
Stroke Apr 2024
Topics: Humans; MELAS Syndrome; Stroke; Muscles; Cognition; Magnetic Resonance Imaging
PubMed: 38362757
DOI: 10.1161/STROKEAHA.123.045984 -
Behavioural Processes Aug 2023Fish stock enhancement has been utilised in Taiwan for more than 30 years, yet the impacts of anthropogenic noise on the enhancement programs remain unknown....
Fish stock enhancement has been utilised in Taiwan for more than 30 years, yet the impacts of anthropogenic noise on the enhancement programs remain unknown. Anthropogenic noise can induce physiological and behavioural changes in many marine fishes. Therefore, we investigated the effects of acute boat noise (from stock enhancement release sites) and chronic noise (from aquaculture processes) on the anti-predator behaviour in three juvenile reef fishes: Epinephelus coioides, Amphiprion ocellaris and Neoglyphidodon melas. We exposed fish to aquaculture noise, boat noise and a combination of both, followed by a predator scare and documented kinematic variables (response latency, response distance, response speed and response duration). For the grouper E. coioides, their response latency decreased in the presence of acute noise, while their response duration increased in the presence of both chronic and acute noise. Among the anemonefish A. ocellaris, all variables remained unaffected by chronic noise, whereas acute noise increased the response distance and response speed. In the case of the black damselfish N. melas, chronic noise decreased the response speed, while acute noise decreased the response latency and response duration. Our results indicate that acute noise had a stronger influence on anti-predator behaviour than chronic noise. This study suggests that acute noise levels at restocking release sites can impact anti-predator behaviour in fishes, potentially altering fitness and likelihood of survival. Such negative effects and interspecific differences must be considered when restocking fish populations.
Topics: Animals; Coral Reefs; MELAS Syndrome; Fishes; Noise; Perciformes; Bass
PubMed: 37364624
DOI: 10.1016/j.beproc.2023.104908 -
Brain Pathology (Zurich, Switzerland) Nov 2023The mitochondrial (m.) 3243A>G mutation is known to be associated with various mitochondrial diseases including mitochondrial myopathy, encephalopathy, lactic acidosis,...
The mitochondrial (m.) 3243A>G mutation is known to be associated with various mitochondrial diseases including mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Their clinical symptoms have been estimated to occur with an increased mitochondrial DNA (mtDNA) heteroplasmy and reduced activity of oxidative phosphorylation (OXPHOS) complexes, but their trends in the central nervous system remain unknown. Six autopsied mutant cases and three disease control cases without the mutation were enrolled in this study. The mutant cases had a disease duration of 1-27 years. Five of six mutant cases were compatible with MELAS. In the mutant cases, cortical lesions including a laminar necrosis were frequently observed in the parietal, lateral temporal, and occipital lobes; less frequently in the frontal lobe including precentral gyrus; and not at all in the medial temporal lobe. The mtDNA heteroplasmy in brain tissue samples of the mutant cases was strikingly high, ranging from 53.8% to 85.2%. The medial temporal lobe was preserved despite an inhospitable environment having high levels of mtDNA heteroplasmy and lactic acid. OXPHOS complex I was widely decreased in the mutant cases. The swelling of smooth muscle cells in the vessels on the leptomeninges, with immunoreactivity (IR) against mitochondria antibody, and a decreased nuclear/cytoplasmic ratio of choroidal epithelial cells were observed in all mutant cases but in none without the mutation. Common neuropathological findings such as cortical laminar necrosis and basal ganglia calcification were not always observed in the mutant cases. A high level of mtDNA heteroplasmy was observed throughout the brain in spite of heterogeneous cortical lesions. A lack of medial temporal lesion, mitochondrial vasculopathy in vessels on the leptomeninges, and an increased cytoplasmic size of epithelial cells in the choroid plexus could be neuropathological hallmarks helpful in the diagnosis of mitochondrial diseases.
Topics: Humans; MELAS Syndrome; Mitochondria; Mitochondrial Diseases; DNA, Mitochondrial; Mutation; Necrosis
PubMed: 37534760
DOI: 10.1111/bpa.13199