scholarly journals Integrated Proteomic and Metabolomic Analyses of the Mitochondrial Neurodegenerative Disease MELAS

2021 ◽  
Author(s):  
Haorong Li ◽  
Martine Uittenbogaard ◽  
Ryan Navarro ◽  
Mustafa Ahmed ◽  
Andrea Gropman ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Complex I ◽  
Tricarboxylic Acid Cycle ◽  
Current Treatment ◽  
Dermal Fibroblasts ◽  
Arginine Infusion ◽  
Data Independent Acquisition ◽  
Mitochondrial Dna Variants ◽  
Clinical Potential ◽  
Cardinal Symptom

MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes) is a progressive neurodegenerative disease caused by pathogenic mitochondrial DNA variants. The pathogenic mechanism of MELAS remains enigmatic due to the exceptional clinical heterogeneity and the obscure genotype-phenotype correlation among MELAS patients. To gain insights into the pathogenic signature of MELAS, we designed a comprehensive strategy integrating proteomics and metabolomics in patient-derived dermal fibroblasts harboring the ultra-rare MELAS pathogenic variant m.14453G>A, specifically affecting the mitochondrial respiratory Complex I. Global proteomics was achieved by data-dependent acquisition (DDA) and verified by data-independent acquisition (DIA) using both Spectronaut and the recently launched MaxDIA platforms. Comprehensive metabolite coverage was achieved for both polar and nonpolar metabolites in both reverse phase and HILIC LC-MS/MS analyses. Our proof-of-principle MELAS study with multi-omics integration revealed OXPHOS dysregulation with a predominant deficiency of Complex I subunits, as well as alterations in key bioenergetic pathways, glycolysis, tricarboxylic acid cycle, and fatty acid β-oxidation. The most clinically relevant discovery is the downregulation of the arginine biosynthesis pathway, likely due to blocked argininosuccinate synthase, which is congruent with the MELAS cardinal symptom of stroke-like episodes and its current treatment by arginine infusion. In conclusion, we demonstrated an integrated proteomic and metabolomic strategy for patient-derived fibroblasts, which has great clinical potential to discover therapeutic targets and design personalized interventions after validation with a larger patient cohort in the future.

scholarly journals Differential posttranslational modification of mitochondrial enzymes corresponds with metabolic suppression during hibernation

2019 ◽  
Vol 317 (2) ◽  
pp. R262-R269 ◽  
Author(s):  
Katherine E. Mathers ◽  
James F. Staples
Keyword(s):  
Body Temperature ◽  
Metabolic Rate ◽  
Posttranslational Modifications ◽  
Complex I ◽  
Tricarboxylic Acid Cycle ◽  
Mitochondrial Metabolism ◽  
Mitochondrial Proteins ◽  
Mitochondrial Enzymes ◽  
Two Dimensional ◽  
Complex Ii

During hibernation, small mammals, including the 13-lined ground squirrel ( Ictidomys tridecemlineatus), cycle between two distinct metabolic states: torpor, where metabolic rate is suppressed by >95% and body temperature falls to ~5°C, and interbout euthermia (IBE), where both metabolic rate and body temperature rapidly increase to euthermic levels. Suppression of whole animal metabolism during torpor is paralleled by rapid, reversible suppression of mitochondrial respiration. We hypothesized that these changes in mitochondrial metabolism are regulated by posttranslational modifications to mitochondrial proteins. Differential two-dimensional gel electrophoresis and two-dimensional blue-native PAGE revealed differences in the isoelectric point of several liver mitochondrial proteins between torpor and IBE. Quadrupole time-of-flight LC/MS and matrix-assisted laser desorption/ionization MS identified these as proteins involved in β-oxidation, the tricarboxylic acid cycle, reactive oxygen species detoxification, and the electron transport system (ETS). Immunoblots revealed that subunit 1 of ETS complex IV was acetylated during torpor but not IBE. Phosphoprotein staining revealed significantly greater phosphorylation of succinyl-CoA ligase and the flavoprotein subunit of ETS complex II in IBE than torpor. In addition, the 75-kDa subunit of ETS complex I was 1.5-fold more phosphorylated in torpor. In vitro treatment with alkaline phosphatase increased the maximal activity of complex I from liver mitochondria isolated from torpid, but not IBE, animals. By contrast, phosphatase treatment decreased complex II activity in IBE but not torpor. These findings suggest that the rapid changes in mitochondrial metabolism in hibernators are mediated by posttranslational modifications of key metabolic enzymes, perhaps by intramitochondrial kinases and deacetylases.

scholarly journals Integrated Proteomic and Metabolomic Analyses of the Mitochondrial Neurodegenerative Disease MELAS

2022 ◽  
Author(s):  
Haorong Li ◽  
Martine Uittenbogaard ◽  
Ryan Navarro ◽  
Mustafa Ahmed ◽  
Andrea Gropman ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Lactic Acidosis ◽  
Neurodegenerative Disease ◽  
Pathogenic Mechanism ◽  
Mitochondrial Encephalomyopathy ◽  
Dna Variants ◽  
Mitochondrial Dna Variants

MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes) is a progressive neurodegenerative disease caused by pathogenic mitochondrial DNA variants. The pathogenic mechanism of MELAS remains enigmatic due to the exceptional clinical...

scholarly journals A novel NDUFA1 mutation leads to a progressive mitochondrial complex I-specific neurodegenerative disease

2009 ◽  
Vol 96 (4) ◽  
pp. 189-195 ◽  
Author(s):  
Prasanth Potluri ◽  
Antonio Davila ◽  
Eduardo Ruiz-Pesini ◽  
Dan Mishmar ◽  
Sean O’Hearn ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Complex I ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex

scholarly journals Huntington's disease research and practice: reflections on the journey made and lessons learned

2011 ◽  
Vol 23 (6) ◽  
pp. 851-857 ◽  
Author(s):  
Anita M.Y. Goh ◽  
Edmond Chiu
Keyword(s):  
Neurodegenerative Disease ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuropsychiatric Symptoms ◽  
Current Treatment ◽  
Lessons Learned ◽  
Monogenic Disorder ◽  
European Origin ◽  
Common Causes ◽  
The Usa

Knowledge about some of the rarer causes of dementia is now quite advanced (Lautenschlager and Martins, 2005), which can in turn inform other more common causes of dementia. Such is the case with the monogenic disorder of Huntington's disease (HD) when compared to, say, Alzheimer's disease (AD). HD is an autosomal dominant hereditary neurodegenerative disease, which involves the basal ganglia, its connections to the frontal lobe and related neural circuits. The onset of HD is typically in mid-life (but onset can range from childhood to old age), with motor, cognitive and neuropsychiatric symptoms. There is currently no cure for this devastating and inevitably fatal neurodegenerative disease, with current treatment approaches being solely symptomatic. The highest frequencies of HD are found in Europe and in those countries whose populations are of predominately European origin such as the USA and Australia (approximately 1 case per 10,000 people).

scholarly journals Metabolic Alterations in Sepsis

2021 ◽  
Vol 10 (11) ◽  
pp. 2412
Author(s):  
Weronika Wasyluk ◽  
Agnieszka Zwolak
Keyword(s):  
Metabolic Disorders ◽  
Potential Role ◽  
Ketone Bodies ◽  
Tricarboxylic Acid Cycle ◽  
Cell Metabolism ◽  
Current Treatment ◽  
Characteristic Change ◽  
Toxic Metabolites ◽  
Life Threatening ◽  
Accumulation Of Lipids

Sepsis is defined as “life-threatening organ dysfunction caused by a dysregulated host response to infection”. Contrary to the older definitions, the current one not only focuses on inflammation, but points to systemic disturbances in homeostasis, including metabolism. Sepsis leads to sepsis-induced dysfunction and mitochondrial damage, which is suggested as a major cause of cell metabolism disorders in these patients. The changes affect the metabolism of all macronutrients. The metabolism of all macronutrients is altered. A characteristic change in carbohydrate metabolism is the intensification of glycolysis, which in combination with the failure of entering pyruvate to the tricarboxylic acid cycle increases the formation of lactate. Sepsis also affects lipid metabolism—lipolysis in adipose tissue is upregulated, which leads to an increase in the level of fatty acids and triglycerides in the blood. At the same time, their use is disturbed, which may result in the accumulation of lipids and their toxic metabolites. Changes in the metabolism of ketone bodies and amino acids have also been described. Metabolic disorders in sepsis are an important area of research, both for their potential role as a target for future therapies (metabolic resuscitation) and for optimizing the current treatment, such as clinical nutrition.

scholarly journals Transcriptome analysis reveals brown adipogenic reprogramming in chemical compound-induced brown adipocytes converted from human dermal fibroblasts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yukimasa Takeda ◽  
Toshikazu Yoshikawa ◽  
Ping Dai
Keyword(s):  
Transcriptome Analysis ◽  
Chemical Compound ◽  
Tricarboxylic Acid Cycle ◽  
Basic Research ◽  
Chemical Conversion ◽  
Dermal Fibroblasts ◽  
Transcriptional Analysis ◽  
Human Dermal Fibroblasts ◽  
Brown Adipocytes ◽  
Beige Adipocytes

AbstractBrown adipogenesis contributes to controlling systemic energy balance by enhancing glucose and lipid consumptions. We have previously reported chemical compound-induced brown adipocytes (ciBAs) directly converted from human dermal fibroblasts using a serum-free medium. In this study, genome-wide transcriptional analysis was performed in ciBAs in comparison with the control fibroblasts. A broad range of integrated gene expression was enhanced in functional groups including tricarboxylic acid cycle, electron transfer chain, triglycerides metabolism, fatty acid and glucose metabolism, and adaptive thermogenesis. The results suggested that the chemical conversion underwent metabolic and mitochondrial reprogramming closely associated with functions in brown/beige adipocytes. Moreover, we also compared the transcriptional changes to those of adipocyte browning in adipose tissue-derived mesenchymal stem cells (AdMSCs). Transcriptome analysis indicated that the same sets of metabolic and mitochondria-related genes were similarly changed in the adipocyte browning. Interestingly, ciBAs more expressed Ucp1, while AdMSC-derived adipocytes predominantly expressed Ucp2. UCP1 protein was also more expressed in ciBAs than in AdMSC-derived adipocytes. Based on the evidence that UCP1, but not UCP2, is responsible for adrenergic thermogenesis, ciBAs could be a promising model for human beige adipocytes applicable for basic research, drug development, and clinical uses.

Eradicating war memories: Neuroscientific reality and ethical concerns

2018 ◽  
Vol 101 (910) ◽  
pp. 69-95 ◽  
Author(s):  
Marijn C. W. Kroes ◽  
Rain Liivoja
Keyword(s):  
Stress Responses ◽  
Current Treatment ◽  
Social Implications ◽  
Post Traumatic Stress ◽  
Military Population ◽  
Traumatic Memories ◽  
Memory Modification ◽  
War Memories ◽  
Moral Duties ◽  
Clinical Potential

AbstractTraumatic memories of war can result in mental disorders such as post-traumatic stress disorder (PTSD). PTSD is characterized by intrusive trauma memories and severe stress responses with devastating personal and societal consequences. Current treatments teach patients to regulate trauma memories, but many experience a return of symptoms even after initially successful treatment. Neuroscience is discovering ways to permanently modify trauma memories and prevent the return of symptoms. Such memory modification techniques (MMTs) have great clinical potential but also important ethical, legal and social implications. In this article, the authors describe PTSD, the role of memory in PTSD, its effects on the brain, and the limitations of current treatment methods. Then, the state of the art of the neuroscience of MMTs is presented. Within this realistic scientific framework the authors will discuss the ethical, legal and social implications of MMTs for the treatment of war-induced PTSD, especially in a military population. Three major sets of issues will be focused on: safety and social justice concerns, concerns about threats to authenticity and identity, and the possible legal and moral duties to retain certain memories. Finally, the article concludes that within scientific reality, concerns are limited and do not outweigh the potential benefits of developing treatments for patients.

Secondary abnormalities of mitochondrial DNA associated with neurodegeneration

1999 ◽  
Vol 66 ◽  
pp. 99-110 ◽  
Author(s):  
S.J. Tabrizi ◽  
A.H.V. Schapira
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dna ◽  
Complex I ◽  
Tricarboxylic Acid Cycle ◽  
Energy Requirement ◽  
Mitochondrial Protein ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
Mtdna Mutation ◽  
Mitochondrial Iron

The central nervous system has a particularly high energy requirement, thus making it very susceptible to defects in mitochondrial function. A number of neurodegenerative diseases, in particular Parkinson's disease (PD), Huntington's disease (HD) and Friedreich's ataxia (FRDA), are associated with mitochondrial dysfunction. The identification of a mitochondrial complex-I defect in PD provides a link between toxin models of the disease, and clues to the pathogenesis of idiopathic PD. We have undertaken genomic transplantation studies involving the transfer of mitochondrial DNA (mtDNA) from PD patients with a complex-I defect to a novel nuclear background. Histochemical, immunohistochemical and functional analysis of the resulting cybrids all showed a pattern in the PD clones indicative of a mtDNA mutation. There is good evidence for the involvement of defective energy metabolism and excitotoxicity in the aetiology of HD. We, and others, have shown a severe deficiency of complex II/III confined to the striatum that mimics the toxin-induced animal models of HD. There is also a milder defect in complex IV in the caudate. The tricarboxylic acid cycle enzyme aconitase is particularly sensitive to inhibition by peroxynitrite and superoxide radicals. We have found this enzyme to be severely decreased in HD caudate, putamen and cortex in a pattern that parallels the severity of neuronal loss seen. We propose a scheme for the role of nitric oxide, free radicals and excitotoxicity in the pathogenesis of HD. FRDA is caused by an expanded GAA repeat in intron 1 of the X25 gene encoding a protein called frataxin. Frataxin is widely expressed and is a mitochondrial protein, although its function is unknown. We have found abnormal magnetic resonance spectroscopy in the skeletal muscle of FRDA patients, which parallels our biochemical findings of reduced complexes I-III in patients' heart and skeletal muscle. There is also reduced aconitase activity in these areas. Increased iron deposition was seen in patients' tissues in a pattern consistent with a mitochondrial location. The mitochondrial iron accumulation, defective respiratory chain activity and aconitase dysfunction suggest that frataxin may be involved in mitochondrial iron regulation. There is also evidence that oxidative stress contributes to cellular toxicity.

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