The multifaceted regulation of mitophagy by endogenous metabolites

Autophagy, Journal Year: 2021, Volume and Issue: 18(6), P. 1216 - 1239

Published: Sept. 29, 2021

Owing to the dominant functions of mitochondria in multiple cellular metabolisms and distinct types regulated cell death, maintaining a functional mitochondrial network is fundamental for homeostasis body fitness response physiological adaptations stressed conditions. The process mitophagy, which dysfunctional or superfluous are selectively engulfed by autophagosome subsequently degraded lysosome, has been well formulated as one major mechanisms quality control. To date, PINK1-PRKN-dependent receptors (including proteins lipids)-dependent pathways have characterized determine mitophagy mammalian cells. highly responsive dynamics endogenous metabolites, including iron-, calcium-, glycolysis-TCA-, NAD+-, amino acids-, fatty cAMP-associated metabolites. Herein, we summarize recent advances toward molecular details regulation We also highlight key regulations shed new light on bidirectional interplay between metabolisms, with attempting provide perspective insight into nutritional intervention metabolic disorders deficit.

Language: Английский

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The role of serotonin within the microbiota-gut-brain axis in the development of Alzheimer’s disease: A narrative review

Ageing Research Reviews, Journal Year: 2022, Volume and Issue: 75, P. 101556 - 101556

Published: Jan. 3, 2022

Alzheimer’s disease (AD) is the most common cause of dementia, accounting for more than 50 million patients worldwide. Current evidence suggests exact mechanism behind this devastating to be multifactorial origin, which seriously complicates quest an effective disease-modifying therapy, as well impedes search strategic preventative measures. Of interest, preclinical studies point serotonergic alterations, either induced via selective serotonin reuptake inhibitors or receptor (ant)agonists, in mitigating AD brain neuropathology next its clinical symptoms, latter being supported by a handful human intervention trials. Additionally, substantial amount trials highlight potential diet, fecal microbiota transplantations, pre- and probiotics modulating brain’s neurotransmitter system, starting from gut. Whether such interventions could truly prevent, reverse slow down progression likewise, should initially tested with mouse models, including sufficient analytical measurements both gut brain. Thereafter, therapeutic effect confirmed rigorously randomized controlled humans, preferentially across continuum, but especially prodromal up mild stages, where high adherence therapies, room noticeable enhancement are feasible still. In end, might aid development comprehensive approach tackle complex disease, since derivatives microbiota-gut-brain axis serve possible biomarkers progression, forming valuable target drug development. narrative review, available concerning orchestrating role within summarized discussed, general considerations future highlighted.

Language: Английский

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Role of indoleamine 2,3-dioxygenase 1 (IDO1) and kynurenine pathway in the regulation of the aging process

Ageing Research Reviews, Journal Year: 2022, Volume and Issue: 75, P. 101573 - 101573

Published: Jan. 24, 2022

Indoleamine 2,3-dioxygenase 1 (IDO1) is activated in chronic inflammatory states, e.g., the aging process and age-related diseases. IDO1 enzyme catabolizes L-tryptophan (L-Trp) into kynurenine (KYN) thus stimulating KYN pathway. The depletion of L-Trp inhibits proliferation immune cells inflamed tissues it also reduces serotonin synthesis predisposing to psychiatric disorders. Interestingly, protein contains two immunoreceptor tyrosine-based inhibitory motifs (ITIM) which trigger suppressive signaling through binding PI3K p110 SHP-1 proteins. This immunosuppressive activity not dependent on catalytic IDO1. its metabolite, kynurenic acid (KYNA), are potent activators aryl hydrocarbon receptor (AhR) can enhance immunosuppression. IDO1-KYN-AhR counteracts excessive pro-inflammatory responses acute inflammation but states has many harmful effects. A low-grade associated with process, a state called inflammaging. There substantial evidence that activation pathway robustly increases process. does only suppress functions effector cells, probably promoting immunosenescence, impairs autophagy, induces cellular senescence, remodels extracellular matrix as well enhancing development osteoporosis vascular I will review function discuss an enhancer

Language: Английский

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UVB-mediated DNA damage induces matrix metalloproteinases to promote photoaging in an AhR- and SP1-dependent manner

JCI Insight, Journal Year: 2022, Volume and Issue: 7(9)

Published: March 22, 2022

It is currently thought that UVB radiation drives photoaging of the skin primarily by generating ROS. In this model, ROS purportedly activates activator protein-1 to upregulate MMPs 1, 3, and 9, which then degrade collagen other extracellular matrix components produce wrinkles. However, these are expressed at relatively low levels correlate poorly with wrinkles, suggesting another mechanism distinct from MMP1/3/9 may be more directly associated photoaging. Here we show MMP2, degrades type IV collagen, abundantly in human skin, increases age sun-exposed correlates robustly aryl hydrocarbon receptor (AhR), a transcription factor activated UV-generated photometabolites. Through mechanistic studies HaCaT immortalized keratinocytes, found AhR, specificity protein 1 (SP1), pathways DNA damage required for induction both MMP2 MMP11 (another MMP implicated photoaging), but not MMP1/3. Last, topical treatment AhR antagonists vitamin B12 folic acid ameliorated UVB-induced wrinkle formation mice while dampening expression skin. These results implicate reveal as potential target preventing

Language: Английский

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Kynurenine Pathway of Tryptophan Metabolism in Neuropsychiatric Disorders: Pathophysiologic and Therapeutic Considerations

Clinical Psychopharmacology and Neuroscience, Journal Year: 2020, Volume and Issue: 18(4), P. 507 - 526

Published: Oct. 30, 2020

Under physiological conditions 95% of the ingested essential amino acid tryptophan is metabolized by kynurenine pathway (KP) to yield ubiquitous co-enzyme nicotinamide adenine dinucleotide, fulfilling cellular energy requirements. Importantly, intermediaries KP exert crucial effects throughout body, including central nervous system. Besides, metabolites are implicated in diverse disease processes such as inflammation/immune disorders, endocrine/metabolic conditions, cancers and neuropsychiatric diseases. A burgeoning body research indicates that plays a pathogenic role major psychiatric diseases like mood disorders schizophrenia. Triggered inflammatory processes, balance between neurotoxic neuroprotective branches disturbed. In preclinical models these discrepancies result behaviors reminiscent depression psychosis. clinical samples, recent studies discovering key abnormalities which incriminate it pathogenesis main disorders. Harnessing this knowledge has potential find biomarkers helpful identifying prognosticating Concurrently, earnest efforts directed towards manipulating hold promise novel pharmacological agents have therapeutic value. manuscript, an in-depth appraisal extant literature done understand working applies It concluded overarching development serve markers new medications based on modulation can bring lasting cures for patients suffering from intractable conditions.

Language: Английский

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Location, Location, Location: Compartmentalization of NAD+ Synthesis and Functions in Mammalian Cells

Trends in Biochemical Sciences, Journal Year: 2020, Volume and Issue: 45(10), P. 858 - 873

Published: June 25, 2020

Language: Английский

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Kynurenine pathway in Parkinson's disease—An update

eNeurologicalSci, Journal Year: 2020, Volume and Issue: 21, P. 100270 - 100270

Published: Sept. 10, 2020

Parkinson's disease (PD) is a complex multi-factorial neurodegenerative disorder where various altered metabolic pathways contribute to the progression of disease. Tryptophan (TRP) major precursor in kynurenine pathway (KP) and it has been discussed vitro studies that metabolites quinolinic acid (QUIN) causes neurotoxicity kynurenic (KYNA) acts as neuroprotectant respectively. More are also focused on effects other KP its enzymes an association with ageing PD pathogenesis. Until now, very few have targeted role genetic mutations abnormal metabolism adverse conditions PD. Therefore, present review gives updated research connection Moreover, emphasizes urge for development biomarkers this would be initiative generating alternative therapeutic approach

Language: Английский

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Regulation of the one carbon folate cycle as a shared metabolic signature of longevity

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: June 9, 2021

Abstract The metabolome represents a complex network of biological events that reflects the physiologic state organism in health and disease. Additionally, specific metabolites metabolic signaling pathways have been shown to modulate animal ageing, but whether there are convergent mechanisms uniting these processes remains elusive. Here, we used high resolution mass spectrometry obtain metabolomic profiles canonical longevity C. elegans identify regulating life span. By leveraging across pathways, found one carbon metabolism folate cycle pervasively regulated common. We observed similar changes long-lived mouse models reduced insulin/IGF signaling. Genetic manipulation pathway enzymes supplementation with reveal regulation shared causal mechanism proteoprotection. Such interventions impact methionine cycle, restriction as an underlying mechanism. This comparative approach reveals key nodes enhance healthy ageing.

Language: Английский

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NAD metabolism: Role in senescence regulation and aging

Aging Cell, Journal Year: 2023, Volume and Issue: 23(1)

Published: July 9, 2023

Abstract The geroscience hypothesis proposes that addressing the biology of aging could directly prevent onset or mitigate severity multiple chronic diseases. Understanding interplay between key aspects biological hallmarks is essential in delivering promises hypothesis. Notably, nucleotide nicotinamide adenine dinucleotide (NAD) interfaces with several aging, including cellular senescence, and changes NAD metabolism have been shown to be involved process. relationship senescence appears complex. On one hand, accumulation DNA damage mitochondrial dysfunction induced by low + can promote development senescence. other state occurs during may inhibit SASP as this secretory phenotype are both highly metabolically demanding. However, date, impact on progression has not fully characterized. Therefore, explore implications replacement therapies, it consider their interactions We propose a comprehensive understanding boosting strategies senolytic agents necessary advance field.

Language: Английский

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The Promise of Niacin in Neurology

Neurotherapeutics, Journal Year: 2023, Volume and Issue: 20(4), P. 1037 - 1054

Published: April 21, 2023

Language: Английский

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