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Molecular and Cellular Neurosciences Sep 2023Mitochondrial dysfunction can arise from genetic defects or environmental exposures and impact a wide range of biological processes. Among these are metabolic pathways... (Review)
Review
Mitochondrial dysfunction can arise from genetic defects or environmental exposures and impact a wide range of biological processes. Among these are metabolic pathways involved in glutamine catabolism, anabolism, and glutamine-glutamate cycling. In recent years, altered glutamine metabolism has been found to play important roles in the pathologic consequences of mitochondrial dysfunction. Glutamine is a pleiotropic molecule, not only providing an alternate carbon source to glucose in certain conditions, but also playing unique roles in cellular communication in neurons and astrocytes. Glutamine consumption and catabolic flux can be significantly altered in settings of genetic mitochondrial defects or exposure to mitochondrial toxins, and alterations to glutamine metabolism appears to play a particularly significant role in neurodegenerative diseases. These include primary mitochondrial diseases like Leigh syndrome (subacute necrotizing encephalopathy) and MELAS (mitochondrial myopathy with encephalopathy, lactic acidosis, and stroke-like episodes), as well as complex age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Pharmacologic interventions targeting glutamine metabolizing and catabolizing pathways appear to provide some benefits in cell and animal models of these diseases, indicating glutamine metabolism may be a clinically relevant target. In this review, we discuss glutamine metabolism, mitochondrial disease, the impact of mitochondrial dysfunction on glutamine metabolic processes, glutamine in neurodegeneration, and candidate targets for therapeutic intervention.
Topics: Animals; Glutamine; MELAS Syndrome; Mitochondria; Neurodegenerative Diseases; Mitochondrial Diseases
PubMed: 37586651
DOI: 10.1016/j.mcn.2023.103887 -
International Journal of Molecular... Mar 2024MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with... (Review)
Review
MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations.
Topics: Humans; MELAS Syndrome; Acidosis, Lactic; Arginine; Stroke; Dietary Supplements
PubMed: 38612442
DOI: 10.3390/ijms25073629 -
Journal of Neurology Feb 2024Mitochondrial myopathy without extraocular muscles involvement (MiMy) represents a distinct form of mitochondrial disorder predominantly affecting proximal/distal or...
OBJECTIVE
Mitochondrial myopathy without extraocular muscles involvement (MiMy) represents a distinct form of mitochondrial disorder predominantly affecting proximal/distal or axial muscles, with its phenotypic, genotypic features, and long-term prognosis poorly understood.
METHODS
A cross-sectional study conducted at a national diagnostic center for mitochondrial disease involved 47 MiMy patients, from a cohort of 643 mitochondrial disease cases followed up at Qilu Hospital from January 1, 2000, to January 1, 2021. We compared the clinical, pathological, and genetic features of MiMy to progressive external ophthalmoplegia (PEO) and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) patients.
RESULTS
MiMy patients demonstrated a more pronounced muscle involvement syndrome, with lower 6MWT scores, higher FSS, and lower BMI compared to PEO and MELAS patients. Serum levels of creatinine kinase (CK), lactate, and growth and differentiation factor 15 (GDF15) were substantially elevated in MiMy patients. Nearly a third (31.9%) displayed signs of subclinical peripheral neuropathy, mostly axonal neuropathy. Muscle biopsies revealed that cytochrome c oxidase strong (COX-s) ragged-red fibers (RRFs) were a typical pathological feature in MiMy patients. Genetic analysis predominantly revealed mtDNA point pathogenic variants (59.6%) and less frequently single (12.8%) or multiple (4.2%) mtDNA deletions. During the follow-up, a majority (76.1%) of MiMy patients experienced stabilization or improvement after therapeutic intervention.
CONCLUSIONS
This study provides a comprehensive profile of MiMy through a large patient cohort, elucidating its unique clinical, genetic, and pathological features. These findings offer significant insights into the diagnostic and therapeutic management of MiMy, ultimately aiming to ameliorate patient outcomes and enhance the quality of life.
Topics: Humans; MELAS Syndrome; Oculomotor Muscles; Cross-Sectional Studies; Quality of Life; Stroke; DNA, Mitochondrial; Acidosis, Lactic; Ophthalmoplegia, Chronic Progressive External
PubMed: 37847292
DOI: 10.1007/s00415-023-12005-5 -
International Journal of Molecular... Dec 2023Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome, caused by a single base substitution in mitochondrial DNA (m.3243A>G), is one...
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome, caused by a single base substitution in mitochondrial DNA (m.3243A>G), is one of the most common maternally inherited mitochondrial diseases accompanied by neuronal damage due to defects in the oxidative phosphorylation system. There is no established treatment. Our previous study reported a superior restoration of mitochondrial function and bioenergetics in mitochondria-deficient cells using highly purified mesenchymal stem cells (RECs). However, whether such exogenous mitochondrial donation occurs in mitochondrial disease models and whether it plays a role in the recovery of pathological neuronal functions is unknown. Here, utilizing induced pluripotent stem cells (iPSC), we differentiated neurons with impaired mitochondrial function from patients with MELAS. MELAS neurons and RECs/mesenchymal stem cells (MSCs) were cultured under contact or non-contact conditions. Both RECs and MSCs can donate mitochondria to MELAS neurons, but RECs are more excellent than MSCs for mitochondrial transfer in both systems. In addition, REC-mediated mitochondrial transfer significantly restored mitochondrial function, including mitochondrial membrane potential, ATP/ROS production, intracellular calcium storage, and oxygen consumption rate. Moreover, mitochondrial function was maintained for at least three weeks. Thus, REC-donated exogenous mitochondria might offer a potential therapeutic strategy for treating neurological dysfunction in MELAS.
Topics: Humans; MELAS Syndrome; Mitochondria; Acidosis, Lactic; DNA, Mitochondrial; Mitochondrial Diseases; Neurons; Mesenchymal Stem Cells
PubMed: 38139018
DOI: 10.3390/ijms242417186 -
Acta Neurologica Taiwanica Mar 2024A 13-year and 4-month-old girl was brought to the emergency department due to fever, dizziness,vomiting, and blurred vision. Laboratory data revealed hyperglycemia with...
A 13-year and 4-month-old girl was brought to the emergency department due to fever, dizziness,vomiting, and blurred vision. Laboratory data revealed hyperglycemia with an HbA1C of 7.3 percent, ketonuria, and lactic acidosis. The initial impression was diabetic ketoacidosis. During admission, recurrent focal impaired awareness seizures were noted, and magnetic resonance imaging of the brain revealed multiple brain infarctions in the bilateral cerebrum. Mitochondrial gene report showed A3243 G with 64 percent heteroplasmy, and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes was diagnosed. At 16 years and 7 months old, recurrence of vomiting and onset of right hemianopia and mild right limb weakness were observed and follow-up T2 images showed massive edema in her left parieto-occipital region. At 16 years and 10 months old, she developed clonus in her left hand associated with an unsteady gait and blurred vision. MRI of the brain revealed recurrent brain infarction, and T2 images showed massive edema of the right parieto-occipital region. MELAS is a rare disease entity and occasionally comorbid with mitochondrial diabetes in childhood. Characteristic radiological features of MELAS include infarction-like lesions over the parieto-occipital or parieto-temporal areas, which help distinguish MELAS from childhood ischemic stroke.
Topics: Humans; Female; Infant; MELAS Syndrome; Diabetic Ketoacidosis; Stroke; Acidosis, Lactic; Ketosis; Edema; Vomiting; Diabetes Mellitus
PubMed: 37853548
DOI: No ID Found -
Nucleic Acids Research Aug 2023Mutations in mitochondrial (mt-)tRNAs frequently cause mitochondrial dysfunction. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes...
Mutations in mitochondrial (mt-)tRNAs frequently cause mitochondrial dysfunction. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonus epilepsy associated with ragged red fibers (MERRF) are major clinical subgroups of mitochondrial diseases caused by pathogenic point mutations in tRNA genes encoded in mtDNA. We previously reported a severe reduction in the frequency of 5-taurinomethyluridine (τm5U) and its 2-thiouridine derivative (τm5s2U) in the anticodons of mutant mt-tRNAs isolated from the cells of patients with MELAS and MERRF, respectively. The hypomodified tRNAs fail to decode cognate codons efficiently, resulting in defective translation of respiratory chain proteins in mitochondria. To restore the mitochondrial activity of MELAS patient cells, we overexpressed MTO1, a τm5U-modifying enzyme, in patient-derived myoblasts. We used a newly developed primer extension method and showed that MTO1 overexpression almost completely restored the τm5U modification of the MELAS mutant mt-tRNALeu(UUR). An increase in mitochondrial protein synthesis and oxygen consumption rate suggested that the mitochondrial function of MELAS patient cells can be activated by restoring the τm5U of the mutant tRNA. In addition, we confirmed that MTO1 expression restored the τm5s2U of the mutant mt-tRNALys in MERRF patient cells. These findings pave the way for epitranscriptomic therapies for mitochondrial diseases.
Topics: Humans; DNA, Mitochondrial; MELAS Syndrome; MERRF Syndrome; Mitochondria; Mutation; RNA, Transfer
PubMed: 36928678
DOI: 10.1093/nar/gkad139 -
JCI Insight Sep 2023Pathogenic mutations in mitochondrial (mt) tRNA genes that compromise oxidative phosphorylation (OXPHOS) exhibit heteroplasmy and cause a range of multisyndromic...
Pathogenic mutations in mitochondrial (mt) tRNA genes that compromise oxidative phosphorylation (OXPHOS) exhibit heteroplasmy and cause a range of multisyndromic conditions. Although mitochondrial disease patients are known to suffer from abnormal immune responses, how heteroplasmic mtDNA mutations affect the immune system at the molecular level is largely unknown. Here, in mice carrying pathogenic C5024T in mt-tRNAAla and in patients with mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) syndrome carrying A3243G in mt-tRNALeu, we found memory T and B cells to have lower pathogenic mtDNA mutation burdens than their antigen-inexperienced naive counterparts, including after vaccination. Pathogenic burden reduction was less pronounced in myeloid compared with lymphoid lineages, despite C5024T compromising macrophage OXPHOS capacity. Rapid dilution of the C5024T mutation in T and B cell cultures could be induced by antigen receptor-triggered proliferation and was accelerated by metabolic stress conditions. Furthermore, we found C5024T to dysregulate CD8+ T cell metabolic remodeling and IFN-γ production after activation. Together, our data illustrate that the generation of memory lymphocytes shapes the mtDNA landscape, wherein pathogenic variants dysregulate the immune response.
Topics: Animals; Mice; Mutation; Receptors, Antigen; DNA, Mitochondrial; Acidosis, Lactic; RNA, Transfer
PubMed: 37681412
DOI: 10.1172/jci.insight.167656 -
American Journal of Ophthalmology Case... Jun 2024To describe examination and findings in a case of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with particular focus on the ocular...
PURPOSE
To describe examination and findings in a case of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with particular focus on the ocular sequelae from diabetes.
OBSERVATIONS
Neovascular glaucoma is not a common manifestation of MELAS.
CONCLUSIONS AND IMPORTANCE
We present a rare case of neovascular glaucoma in a patient with MELAS with a history of diabetes, hearing loss, and macular dystrophy. MELAS should be suspected in patients with this constellation of symptoms.
PubMed: 38707951
DOI: 10.1016/j.ajoc.2024.102064 -
Neurology. Genetics Aug 2023Stroke-like episodes (SLEs) in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome are often misdiagnosed as acute...
BACKGROUND AND OBJECTIVES
Stroke-like episodes (SLEs) in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome are often misdiagnosed as acute ischemic stroke (AIS). We aimed to determine unique clinical and neuroimaging features for SLEs and formulate diagnostic criteria.
METHODS
We retrospectively identified patients with MELAS admitted for SLEs between January 2012 and December 2021. Clinical features and imaging findings were compared with a cohort of patients who presented with AIS and similar lesion topography. A set of criteria was formulated and then tested by a blinded rater to evaluate diagnostic performance.
RESULTS
Eleven MELAS patients with 17 SLE and 21 AISs were included. Patients with SLEs were younger (median 45 [37-60] vs 77 [68-82] years, < 0.01) and had a lower body mass index (18 ± 2.6 vs 29 ± 4, < 0.01), more commonly reported hearing loss (91% vs 5%, < 0.01), and more commonly presented with headache and/or seizures (41% vs 0%, < 0.01). The earliest neuroimaging test performed at presentation was uniformly a noncontrast CT. Two main patterns of lesion topography with a stereotypical spatiotemporal evolution were identified-an anterior pattern (7/21, 41%) starting at the temporal operculum and spreading to the peripheral frontal cortex and a posterior pattern (10/21, 59%) starting at the cuneus/precuneus and spreading to the lateral occipital and parietal cortex. Other distinguishing features for SLEs vs AIS were cerebellar atrophy (91% vs 19%, < 0.01), previous cortical lesions with typical SLE distribution (46% vs 9%, = 0.03), acute lesion tissue hyperemia and venous engorgement on CT angiography (CTA) (45% vs 0%, < 0.01), and no large vessel occlusion on CTA (0% vs 100%, < 0.01). Based on these clinicoradiologic features, a set of diagnostic criteria were constructed for possible SLE (sensitivity 100%, specificity 81%, AUC 0.905) and probable SLE (sensitivity 88%, specificity 95%, AUC 0.917).
DISCUSSION
Clinicoradiologic criteria based on simple anamnesis and a CT scan at presentation can accurately diagnose SLE and lead to early administration of appropriate therapy.
CLASSIFICATION OF EVIDENCE
This study provides Class III evidence that an algorithm using clinical and imaging features can differentiate stroke-like episodes due to MELAS from acute ischemic strokes.
PubMed: 37426458
DOI: 10.1212/NXG.0000000000200082