Clinical Insights into Mitochondrial Neurodevelopmental and Neurodegenerative Disorders: Their Biosignatures from Mass Spectrometry-Based Metabolomics

Mitochondria are dynamic multitask organelles that function as hubs for many metabolic pathways. They produce most ATP via the oxidative phosphorylation pathway, a critical pathway that the brain relies on its energy need associated with its numerous functions, such as synaptic homeostasis and plasticity. Therefore, mitochondrial dysfunction is a prevalent pathological hallmark of many neurodevelopmental and neurodegenerative disorders resulting in altered neurometabolic coupling. With the advent of mass spectrometry (MS) technology, MS-based metabolomics provides an emerging mechanistic understanding of their global and dynamic metabolic signatures. In this review, we discuss the pathogenetic causes of mitochondrial metabolic disorders and the recent MS-based metabolomic advances on their metabolomic remodeling. We conclude by exploring the MS-based metabolomic functional insights into their biosignatures to improve diagnostic platforms, stratify patients, and design novel targeted therapeutic strategies.

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Neuroprotective Potential of GDF11: Myth or Reality?

International Journal of Molecular Sciences ◽

10.3390/ijms20143563 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3563 ◽

Cited By ~ 1

Author(s):

Luc Rochette ◽

Gabriel Malka

Keyword(s):

Neurodegenerative Diseases ◽

Blood Plasma ◽

Neurodegenerative Disorders ◽

Brain Aging ◽

Therapeutic Strategies ◽

Blood Concentrations ◽

Age Related ◽

Novel Therapeutic Strategies ◽

The Brain ◽

Novel Therapeutic

In the brain, aging is accompanied by cellular and functional deficiencies that promote vulnerability to neurodegenerative disorders. In blood plasma from young and old animals, various factors such as growth differentiation factor 11 (GDF11), whose levels are elevated in young animals, have been identified. The blood concentrations of these factors appear to be inversely correlated with the age-related decline of neurogenesis. The identification of GDF11 as a “rejuvenating factor” opens up perspectives for the treatment of neurodegenerative diseases. As a pro-neurogenic and pro-angiogenic agent, GDF11 may constitute a basis for novel therapeutic strategies.

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Insulin in Central Nervous System: More than Just a Peripheral Hormone

Journal of Aging Research ◽

10.1155/2012/384017 ◽

2012 ◽

Vol 2012 ◽

pp. 1-21 ◽

Cited By ~ 122

Author(s):

Ana I. Duarte ◽

Paula I. Moreira ◽

Catarina R. Oliveira

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neurodegenerative Disorders ◽

Intracellular Signaling ◽

Therapeutic Strategies ◽

Healthy Longevity ◽

Complex Interactions ◽

Brain Insulin ◽

Age Related ◽

The Brain

Insulin signaling in central nervous system (CNS) has emerged as a novel field of research since decreased brain insulin levels and/or signaling were associated to impaired learning, memory, and age-related neurodegenerative diseases. Thus, besides its well-known role in longevity, insulin may constitute a promising therapy against diabetes- and age-related neurodegenerative disorders. More interestingly, insulin has been also faced as the potential missing link between diabetes and aging in CNS, with Alzheimer's disease (AD) considered as the “brain-type diabetes.” In fact, brain insulin has been shown to regulate both peripheral and central glucose metabolism, neurotransmission, learning, and memory and to be neuroprotective. And a future challenge will be to unravel the complex interactions between aging and diabetes, which, we believe, will allow the development of efficient preventive and therapeutic strategies to overcome age-related diseases and to prolong human “healthy” longevity. Herewith, we aim to integrate the metabolic, neuromodulatory, and neuroprotective roles of insulin in two age-related pathologies: diabetes and AD, both in terms of intracellular signaling and potential therapeutic approach.

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Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Bioscience Reports ◽

10.1042/bsr20150295 ◽

2016 ◽

Vol 36 (2) ◽

Cited By ~ 34

Author(s):

Abena Nsiah-Sefaa ◽

Matthew McKenzie

Keyword(s):

Fatty Acid ◽

Oxidative Phosphorylation ◽

Mitochondrial Disease ◽

Metabolic Pathways ◽

Live Births ◽

Mitochondrial Fatty Acid ◽

Physical Interactions ◽

The Brain ◽

Combined Defects

Mitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP. Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.

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Iron and Neurodegeneration: From Cellular Homeostasis to Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2012/128647 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 38

Author(s):

Liliana Batista-Nascimento ◽

Catarina Pimentel ◽

Regina Andrade Menezes ◽

Claudina Rodrigues-Pousada

Keyword(s):

Oxidative Stress ◽

Saccharomyces Cerevisiae ◽

Neurodegenerative Disorders ◽

Neurological Disorders ◽

Genetic Factors ◽

Therapeutic Strategies ◽

Neuronal Dysfunction ◽

Eukaryotic Organism ◽

The Brain

Accumulation of iron (Fe) is often detected in the brains of people suffering from neurodegenerative diseases. High Fe concentrations have been consistently observed in Parkinson’s, Alzheimer’s, and Huntington’s diseases; however, it is not clear whether this Fe contributes to the progression of these diseases. Other conditions, such as Friedreich’s ataxia or neuroferritinopathy are associated with genetic factors that cause Fe misregulation. Consequently, excessive intracellular Fe increases oxidative stress, which leads to neuronal dysfunction and death. The characterization of the mechanisms involved in the misregulation of Fe in the brain is crucial to understand the pathology of the neurodegenerative disorders and develop new therapeutic strategies.Saccharomyces cerevisiae, as the best understood eukaryotic organism, has already begun to play a role in the neurological disorders; thus it could perhaps become a valuable tool also to study the metalloneurobiology.

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Brain Drug Delivery: Overcoming the Blood-brain Barrier to Treat Tauopathies

Current Pharmaceutical Design ◽

10.2174/1381612826666200316130128 ◽

2020 ◽

Vol 26 (13) ◽

pp. 1448-1465 ◽

Cited By ~ 1

Author(s):

Jozef Hanes ◽

Eva Dobakova ◽

Petra Majerova

Keyword(s):

Drug Delivery ◽

Blood Brain Barrier ◽

Neurodegenerative Disorders ◽

Brain Barrier ◽

Neuronal Function ◽

Brain Drug Delivery ◽

Naturally Occurring ◽

Blood Brain ◽

Traditional Approaches ◽

The Brain

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. Yet, these natural functions possessed by BBB represent a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics’ delivery through the BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with advanced medical techniques. Their limitations and benefits are discussed.

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Neurometabolic Diseases in Children: Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy Features

Current Medical Imaging Formerly Current Medical Imaging Reviews ◽

10.2174/1573405613666171123152451 ◽

2019 ◽

Vol 15 (3) ◽

pp. 255-268

Author(s):

Direnç Özlem Aksoy ◽

Alpay Alkan

Keyword(s):

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Metabolic Pathways ◽

Wide Spectrum ◽

Demyelinating Diseases ◽

Resonance Spectroscopy ◽

Resonance Imaging ◽

Neurometabolic Disorders ◽

Brain Involvement ◽

The Brain

Background: Neurometabolic diseases are a group of diseases secondary to disorders in different metabolic pathways, which lead to white and/or gray matter of the brain involvement. </P><P> Discussion: Neurometabolic disorders are divided in two groups as dysmyelinating and demyelinating diseases. Because of wide spectrum of these disorders, there are many different classifications of neurometabolic diseases. We used the classification according to brain involvement areas. In radiological evaluation, MRI provides useful information for these disseases. Conclusion: Magnetic Resonance Spectroscopy (MRS) provides additional metabolic information for diagnosis and follow ups in childhood with neurometabolic diseases.

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Metabolic Regulation and Related Molecular Mechanisms in Various Stem Cell Functions

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666200512105347 ◽

2020 ◽

Vol 15 (6) ◽

pp. 531-546 ◽

Cited By ~ 1

Author(s):

Hwa-Yong Lee ◽

In-Sun Hong

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Oxidative Phosphorylation ◽

Metabolic Pathways ◽

Critical Role ◽

The Self ◽

Specific Cell ◽

Differentiation Potential ◽

Self Renewal ◽

Cell Functions

Recent studies on the mechanisms that link metabolic changes with stem cell fate have deepened our understanding of how specific metabolic pathways can regulate various stem cell functions during the development of an organism. Although it was originally thought to be merely a consequence of the specific cell state, metabolism is currently known to play a critical role in regulating the self-renewal capacity, differentiation potential, and quiescence of stem cells. Many studies in recent years have revealed that metabolic pathways regulate various stem cell behaviors (e.g., selfrenewal, migration, and differentiation) by modulating energy production through glycolysis or oxidative phosphorylation and by regulating the generation of metabolites, which can modulate multiple signaling pathways. Therefore, a more comprehensive understanding of stem cell metabolism could allow us to establish optimal culture conditions and differentiation methods that would increase stem cell expansion and function for cell-based therapies. However, little is known about how metabolic pathways regulate various stem cell functions. In this context, we review the current advances in metabolic research that have revealed functional roles for mitochondrial oxidative phosphorylation, anaerobic glycolysis, and oxidative stress during the self-renewal, differentiation and aging of various adult stem cell types. These approaches could provide novel strategies for the development of metabolic or pharmacological therapies to promote the regenerative potential of stem cells and subsequently promote their therapeutic utility.

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Role of Flavonoids in Neurodegenerative Disorders with Special Emphasis on Tangeritin

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666190916141934 ◽

2019 ◽

Vol 18 (8) ◽

pp. 581-597 ◽

Cited By ~ 1

Author(s):

Ambreen Fatima ◽

Yasir Hasan Siddique

Keyword(s):

Medicinal Plants ◽

Mechanism Of Action ◽

Neurodegenerative Disorders ◽

Treatment Strategies ◽

Dietary Supplementation ◽

Plant Polyphenols ◽

Promising Candidate ◽

Naturally Occurring ◽

The Brain

Flavonoids are naturally occurring plant polyphenols found universally in all fruits, vegetables and medicinal plants. They have emerged as a promising candidate in the formulation of treatment strategies for various neurodegenerative disorders. The use of flavonoid rich plant extracts and food in dietary supplementation have shown favourable outcomes. The present review describes the types, properties and metabolism of flavonoids. Neuroprotective role of various flavonoids and the possible mechanism of action in the brain against the neurodegeneration have been described in detail with special emphasis on the tangeritin.

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Neurodegenerative Proteinopathies in the Proteoform Spectrum—Tools and Challenges

International Journal of Molecular Sciences ◽

10.3390/ijms22031085 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1085

Author(s):

Aneeqa Noor ◽

Saima Zafar ◽

Inga Zerr

Keyword(s):

Mass Spectrometry ◽

Neurodegenerative Disorders ◽

Gel Electrophoresis ◽

Large Fraction ◽

Imaging Mass Spectrometry ◽

Living Tissue ◽

Disease Prognosis ◽

Highly Sensitive ◽

Jakob Disease ◽

Hydrophobic Nature

Proteinopathy refers to a group of disorders defined by depositions of amyloids within living tissue. Neurodegenerative proteinopathies, including Alzheimer’s disease, Parkinson’s disease, Creutzfeldt–Jakob disease, and others, constitute a large fraction of these disorders. Amyloids are highly insoluble, ordered, stable, beta-sheet rich proteins. The emerging theory about the pathophysiology of neurodegenerative proteinopathies suggests that the primary amyloid-forming proteins, also known as the prion-like proteins, may exist as multiple proteoforms that contribute differentially towards the disease prognosis. It is therefore necessary to resolve these disorders on the level of proteoforms rather than the proteome. The transient and hydrophobic nature of amyloid-forming proteins and the minor post-translational alterations that lead to the formation of proteoforms require the use of highly sensitive and specialized techniques. Several conventional techniques, like gel electrophoresis and conventional mass spectrometry, have been modified to accommodate the proteoform theory and prion-like proteins. Several new ones, like imaging mass spectrometry, have also emerged. This review aims to discuss the proteoform theory of neurodegenerative disorders along with the utility of these proteomic techniques for the study of highly insoluble proteins and their associated proteoforms.

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