Dataset Information

Dysfunction of Mitochondrial Ca²⁺ Regulatory Machineries in Brain Aging and Neurodegenerative Diseases.

ABSTRACT: Calcium ions (Ca²⁺) play critical roles in neuronal processes, such as signaling pathway activation, transcriptional regulation, and synaptic transmission initiation. Therefore, the regulation of Ca²⁺ homeostasis is one of the most important processes underlying the basic cellular viability and function of the neuron. Multiple components, including intracellular organelles and plasma membrane Ca²⁺-ATPase, are involved in neuronal Ca²⁺ control, and recent studies have focused on investigating the roles of mitochondria in synaptic function. Numerous mitochondrial Ca²⁺ regulatory proteins have been identified in the past decade, with studies demonstrating the tissue- or cell-type-specific function of each component. The mitochondrial calcium uniporter and its binding subunits are major inner mitochondrial membrane proteins contributing to mitochondrial Ca²⁺ uptake, whereas the mitochondrial Na⁺/Ca²⁺ exchanger (NCLX) and mitochondrial permeability transition pore (mPTP) are well-studied proteins involved in Ca²⁺ extrusion. The level of cytosolic Ca²⁺ and the resulting characteristics of synaptic vesicle release properties are controlled via mitochondrial Ca²⁺ uptake and release at presynaptic sites, while in dendrites, mitochondrial Ca²⁺ regulation affects synaptic plasticity. During brain aging and the progress of neurodegenerative disease, mitochondrial Ca²⁺ mishandling has been observed using various techniques, including live imaging of Ca²⁺ dynamics. Furthermore, Ca²⁺ dysregulation not only disrupts synaptic transmission but also causes neuronal cell death. Therefore, understanding the detailed pathophysiological mechanisms affecting the recently discovered mitochondrial Ca²⁺ regulatory machineries will help to identify novel therapeutic targets. Here, we discuss current research into mitochondrial Ca²⁺ regulatory machineries and how mitochondrial Ca²⁺ dysregulation contributes to brain aging and neurodegenerative disease.

SUBMITTER: Jung H

PROVIDER: S-EPMC7775422 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Dysfunction of Mitochondrial Ca2+ Regulatory Machineries in Brain Aging and Neurodegenerative Diseases.

Jung Hyunsu H Kim Su Yeon SY Canbakis Cecen Fatma Sema FS Cho Yongcheol Y Kwon Seok-Kyu SK

Frontiers in cell and developmental biology 20201218

Calcium ions (Ca2+) play critical roles in neuronal processes, such as signaling pathway activation, transcriptional regulation, and synaptic transmission initiation. Therefore, the regulation of Ca2+ homeostasis is one of the most important processes underlying the basic cellular viability and function of the neuron. Multiple components, including intracellular organelles and plasma membrane Ca2+-ATPase, are involved in neuronal Ca2+ control, and rece ...[more]

PMID: 33392190

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Project description:Mitochondria are the repository for various metabolites involved in diverse energy-generating processes, like the TCA cycle, oxidative phosphorylation, and metabolism of amino acids, fatty acids, and nucleotides, which rely significantly on flavoenzymes, such as oxidases, reductases, and dehydrogenases. Flavoenzymes are functionally dependent on biologically active flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN), which are derived from the dietary component riboflavin, a water soluble vitamin. Riboflavin regulates the structure and function of flavoenzymes through its cofactors FMN and FAD and, thus, protects the cells from oxidative stress and apoptosis. Hence, it is not surprising that any disturbance in riboflavin metabolism and absorption of this vitamin may have consequences on cellular FAD and FMN levels, resulting in mitochondrial dysfunction by reduced energy levels, leading to riboflavin associated disorders, like cataracts, neurodegenerative and cardiovascular diseases, etc. Furthermore, mutations in either nuclear or mitochondrial DNA encoding for flavoenzymes and flavin transporters significantly contribute to the development of various neurological disorders. Moreover, recent studies have evidenced that riboflavin supplementation remarkably improved the clinical symptoms, as well as the biochemical abnormalities, in patients with neuronopathies, like Brown-Vialetto-Van-Laere syndrome (BVVLS) and Fazio-Londe disease. This review presents an updated outlook on the cellular and molecular mechanisms of neurodegenerative disorders in which riboflavin deficiency leads to dysfunction in mitochondrial energy metabolism, and also highlights the significance of riboflavin supplementation in aforementioned disease conditions. Thus, the outcome of this critical assessment may exemplify a new avenue to enhance the understanding of possible mechanisms in the progression of neurodegenerative diseases and may provide new rational approaches of disease surveillance and treatment.

Project description:BackgroundAging and neurodegenerative diseases are typical metabolic-related processes. As a metabolism-related long non-coding RNA, EPB41L4A-AS has been reported to be potentially involved in the development of brain aging and neurodegenerative diseases. In this study, we sought to reveal the mechanisms of EPB41L4A-AS in aging and neurodegenerative diseases.MethodsHuman hippocampal gene expression profiles downloaded from the Genotype-Tissue Expression database were analyzed to obtain age-stratified differentially expressed genes; a weighted correlation network analysis algorithm was then used to construct a gene co-expression network of these differentially expressed genes to obtain gene clustering modules. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, protein-protein interaction network, and correlation analysis were used to reveal the role of EPB41L4A-AS1. The mechanism was verified using Gene Expression Omnibus dataset GSE5281 and biological experiments (construction of cell lines, Real-time quantitative PCR, Western blot, measurement of ATP and NAD+ levels, nicotinamide riboside treatment, Chromatin Immunoprecipitation) in neurons and glial-derived cells.ResultsEPB41L4A-AS1 was downregulated in aging and Alzheimer's disease. EPB41L4A-AS1 related genes were found to be enriched in the electron transport chain and NAD+ synthesis pathway. Furthermore, these genes were highly associated with neurodegenerative diseases and positively correlated with EPB41L4A-AS1. In addition, biological experiments proved that the downregulation of EPB41L4A-AS1 could reduce the expression of these genes via histone H3 lysine 27 acetylation, resulting in decreased NAD+ and ATP levels, while EPB41L4A-AS1 overexpression and nicotinamide riboside treatment could restore the NAD+ and ATP levels.ConclusionsDownregulation of EPB41L4A-AS1 not only disturbs NAD+ biosynthesis but also affects ATP synthesis. As a result, the high demand for NAD+ and ATP in the brain cannot be met, promoting the development of brain aging and neurodegenerative diseases. However, overexpression of EPB41L4A-AS1 and nicotinamide riboside, a substrate of NAD+ synthesis, can reduce EPB41L4A-AS1 downregulation-mediated decrease of NAD+ and ATP synthesis. Our results provide new perspectives on the mechanisms underlying brain aging and neurodegenerative diseases.

Dataset Information

Dysfunction of Mitochondrial Ca²⁺ Regulatory Machineries in Brain Aging and Neurodegenerative Diseases.

Publications

Dysfunction of Mitochondrial Ca<sup>2+</sup> Regulatory Machineries in Brain Aging and Neurodegenerative Diseases.

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