NAD+ in Brain Aging and Neurodegenerative Disorders

Cell Metabolism, Год журнала: 2019, Номер 30(4), С. 630 - 655

Опубликована: Окт. 1, 2019

NAD+ is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD+-dependent enzymes are synaptic plasticity neuronal resistance. Here, we review emerging findings that reveal key roles for related metabolites the adaptation of neurons to wide range physiological stressors counteracting processes neurodegenerative diseases, such as those occurring Alzheimer's, Parkinson's, Huntington amyotrophic lateral sclerosis. Advances understanding molecular mechanisms NAD+-based resilience will lead novel approaches facilitating healthy brain aging treatment neurological disorders. Nicotinamide adenine dinucleotide (NAD+) fundamental molecule health disease, it central several bioenergetic functions. synthesized via three major pathways, including de novo biosynthesis, Preiss-Handler pathway, salvage pathway (Figure 1). 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DiAntonio Milbrandt toll/interleukin-1 possesses intrinsic cleavage promotes pathological axonal degeneration.Neuron. 93: 1334-1343Abstract (18) An, 2018Pan Z.G. X.S. deletion restrains NAFLD fat diet (HFD) reducing lipid accumulation.Biochem. Biophys. 2018; 498: 416-423Crossref (7) cyclase glycohydrolase activities, estimated Michaelis constant (Km) 24 μM, similar other known NAD+-consumers (PARP1, 50–97 μM; SIRT1, 94–96 15–25 μM) (Cantó 2015Cantó Menzies K.J. Auwerx homeostasis: balancing act nucleus.Cell 22: 31-53Abstract degeneration therefore potential target intervention holds signal, clear. SIRTS, CD38/CD157, compete each consume NAD+; thus, enzyme impair activities enzymes. interrelationships reviewed recently equilibrium synthesis, consumption, cytoplasm, nucleus, Golgi apparatus. Two expression subcellular-specific NAD+-synthetic transporters metabolites. convert NAD+. include

Язык: Английский

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Mitophagy, Mitochondrial Homeostasis, and Cell Fate

Frontiers in Cell and Developmental Biology, Год журнала: 2020, Номер 8

Опубликована: Июнь 24, 2020

Mitochondria are highly plastic and dynamic organelles that have graded responses to the changing cellular, environmental developmental cues. undergo constant mitochondrial fission fusion, biogenesis mitophagy, which coordinately control morphology, quantity, quality, turnover inheritance. Mitophagy is a cellular process selectively removes aged damaged mitochondria via specific sequestration engulfment of for subsequent lysosomal degradation. It plays pivotal role reinstate homeostasis in normal physiology conditions stress. Damaged may either instigate innate immunity through overproduction ROS or release mtDNA, trigger cell death cytochrome c other apoptogenic factors when damage beyond repair. Distinct molecular machineries signaling pathways found regulate these dynamics behaviors. less clear how behaviors coordinated at levels. BCL2 family proteins interact within members outer membrane permeabilization apoptosis. They were also described as global regulators fate their interaction with distinct partners including Drp1, mitofusins, PGAM5 even LC3 involved In this review, we summarize recent findings on governing mitophagy its coordination behaviors, together determine fate.

Язык: Английский

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Mitophagy and Neuroprotection

Trends in Molecular Medicine, Год журнала: 2019, Номер 26(1), С. 8 - 20

Опубликована: Июль 30, 2019

Язык: Английский

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The different autophagy degradation pathways and neurodegeneration

Neuron, Год журнала: 2022, Номер 110(6), С. 935 - 966

Опубликована: Фев. 7, 2022

Язык: Английский

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Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities

Cell Death and Differentiation, Год журнала: 2021, Номер 28(2), С. 570 - 590

Опубликована: Янв. 7, 2021

Abstract Neurodegenerative diseases are characterised by progressive damage to the nervous system including selective loss of vulnerable populations neurons leading motor symptoms and cognitive decline. Despite millions people being affected worldwide, there still no drugs that block neurodegenerative process stop or slow disease progression. Neuronal death in these is often linked misfolded proteins aggregate within brain (proteinopathies) as a result disease-related gene mutations abnormal protein homoeostasis. There two major degradation pathways rid cell unwanted prevent their accumulation maintain health cell: ubiquitin–proteasome autophagy–lysosomal pathway. Both degradative depend on modification targets with ubiquitin. Aging primary risk factor most Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis. With aging general reduction proteasomal autophagy, consequent increase potentially neurotoxic aggregates β-amyloid, tau, α-synuclein, SOD1 TDP-43. An over-looked yet component ubiquitin, implicating either an adaptive response toxic evidence dysregulated ubiquitin-mediated driving aggregation. In addition, non-degradative ubiquitin signalling critical for homoeostatic mechanisms fundamental neuronal function survival, mitochondrial homoeostasis, receptor trafficking DNA responses, whilst also playing role inflammatory processes. This review will discuss current understanding ubiquitin-dependent processes emergence target development much needed new treat disease.

Язык: Английский

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The role of mitochondrial dysfunction in Alzheimer's disease pathogenesis

Alzheimer s & Dementia, Год журнала: 2022, Номер 19(1), С. 333 - 342

Опубликована: Май 6, 2022

Abstract To promote new thinking of the pathogenesis Alzheimer's disease (AD), we examine central role mitochondrial dysfunction in AD. Pathologically, AD is characterized by progressive neuronal loss and biochemical abnormalities including dysfunction. Conventional has dictated that driven amyloid beta pathology, per Amyloid Cascade Hypothesis. However, underlying mechanism how leads to cognitive decline remains unclear. A model correctly identifying critical needed for development effective therapeutics. Mitochondrial closely linked core pathological feature AD: Targeting mitochondria associated proteins may hold promise strategies disease‐modifying therapies. According Hypothesis, drives AD, as baseline function change rates influence progression decline. Highlights The Model does not readily account various parameters with (AD). unified greatly inform successful Mitochondria play a key maintenance optimal synaptic function, be primary cause promising target therapeutic strategies.

Язык: Английский

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The mitophagy pathway and its implications in human diseases

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Авг. 16, 2023

Abstract Mitochondria are dynamic organelles with multiple functions. They participate in necrotic cell death and programmed apoptotic, crucial for metabolism survival. Mitophagy serves as a cytoprotective mechanism to remove superfluous or dysfunctional mitochondria maintain mitochondrial fine-tuning numbers balance intracellular homeostasis. Growing evidences show that mitophagy, an acute tissue stress response, plays important role maintaining the health of network. Since timely removal abnormal is essential survival, cells have evolved variety mitophagy pathways ensure can be activated time under various environments. A better understanding diseases treatment therapeutic target design. In this review, we summarize molecular mechanisms mitophagy-mediated elimination, how maintains homeostasis at system levels organ, what alterations related development diseases, including neurological, cardiovascular, pulmonary, hepatic, renal disease, etc., recent advances. Finally, potential clinical applications outline conditions regulators enter trials. Research advances signaling transduction will developing new strategies precision medicine.

Язык: Английский

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Amelioration of Alzheimer’s disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow

Nature Biomedical Engineering, Год журнала: 2022, Номер 6(1), С. 76 - 93

Опубликована: Янв. 6, 2022

Abstract A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer’s disease (AD). Strategies for treating impaired mitophagy would benefit from the identification modulators. Here we report combined use unsupervised machine learning (involving vector representations molecular structures, pharmacophore fingerprinting conformer fingerprinting) a cross-species approach screening experimental validation new mitophagy-inducing compounds. From library naturally occurring compounds, workflow allowed us identify 18 small molecules, among them two potent inducers (Kaempferol Rhapontigenin). In nematode rodent models AD, show that both increased survival functionality glutamatergic cholinergic neurons, abrogated amyloid-β tau pathologies, improved animals’ memory. Our findings suggest existence conserved mechanism memory loss across AD models, this being mediated by defective mitophagy. The computational–experimental might help uncover modulators stimulate neuronal health brain homeostasis.

Язык: Английский

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Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases

Cells, Год журнала: 2020, Номер 9(1), С. 150 - 150

Опубликована: Янв. 8, 2020

Mitochondrial dysfunction is a central aspect of aging and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis, Huntington’s disease. Mitochondria are the main cellular energy powerhouses, supplying most ATP by oxidative phosphorylation, which required to fuel essential neuronal functions. Efficient removal aged dysfunctional mitochondria through mitophagy, cargo-selective autophagy, crucial for mitochondrial maintenance health. Mechanistic studies into mitophagy have highlighted an integrated elaborate network that can regulate turnover. In this review, we provide updated overview recent discoveries advancements on pathways discuss molecular mechanisms underlying defects in disease other age-related as well therapeutic potential mitophagy-enhancing strategies combat these disorders.

Язык: Английский

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Mechanisms and roles of mitophagy in neurodegenerative diseases

CNS Neuroscience & Therapeutics, Год журнала: 2019, Номер 25(7), С. 859 - 875

Опубликована: Май 2, 2019

Mitochondria are double-membrane-encircled organelles existing in most eukaryotic cells and playing important roles energy production, metabolism, Ca2+ buffering, cell signaling. Mitophagy is the selective degradation of mitochondria by autophagy. can effectively remove damaged or stressed mitochondria, which essential for cellular health. Thanks to implementation genetics, biology, proteomics approaches, we beginning understand mechanisms mitophagy, including ubiquitin-dependent receptor-dependent signals on triggering mitophagy. Mitochondrial dysfunction defective mitophagy have been broadly associated with neurodegenerative diseases. This review aimed at summarizing higher organisms pathogenesis Although many studies devoted elucidating process, a deeper understanding leading defects diseases required development new therapeutic interventions, taking into account multifactorial nature phenotypic heterogeneity patients.

Язык: Английский

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