Mitochondrial signalling and homeostasis: from cell biology to neurological disease

Trends in Neurosciences, Journal Year: 2023, Volume and Issue: 46(2), P. 137 - 152

Published: Jan. 10, 2023

Efforts to understand how mitochondrial dysfunction contributes neurodegeneration have primarily focussed on the role of mitochondria in neuronal energy metabolism. However, progress understanding etiological nature emerging functions has yielded new ideas about basis neurological disease. Studies aimed at deciphering signal through interorganellar contacts, vesicular trafficking, and metabolic transmission revealed that regulation immunometabolism, cell death, organelle dynamics, neuroimmune interplay are critical determinants neural health. Moreover, homeostatic mechanisms exist protect health turnover via nanoscale proteostasis lysosomal degradation become integrated within signalling pathways support plasticity stress responses nervous system. This review highlights these distinct converge influence contribute disease pathology.

Language: Английский

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Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 1, 2024

Autophagy is primarily activated by cellular stress, such as starvation or mitochondrial damage. However, stress-independent autophagy unclear mechanisms in several cell types, thymic epithelial cells (TECs). Here we report that the protein, C15ORF48, a critical inducer of autophagy. Mechanistically, C15ORF48 reduces membrane potential and lowers intracellular ATP levels, thereby activating AMP-activated protein kinase its downstream Unc-51-like 1. Interestingly, C15ORF48-dependent induction upregulates glutathione promoting survival reducing oxidative stress. Mice deficient C15orf48 show reduction TECs, but not typical starvation-induced skeletal muscles. Moreover,

Language: Английский

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Mitochondrial Dysfunction as the Major Basis of Brain Aging

Biomolecules, Journal Year: 2024, Volume and Issue: 14(4), P. 402 - 402

Published: March 26, 2024

The changes in the properties of three biological events that occur with cerebral aging are discussed. These adverse already begin to develop early mid-life and gradually become more pronounced senescence. Essentially, they reflections progressive decline effectiveness key processes, resulting deviation essential biochemical trajectories ineffective ultimately harmful variants these programs. emphasis this review is major role played by mitochondria transition important processes toward deleterious as brain proceeds. immune system: shift away from an efficient response a unfocused, continuing inflammatory condition. Such state both harmful. Reactive oxygen species intracellular signaling systems. Additionally, microglial phagocytic activity utilizing short lived reactive contribute removal aberrant or dead cells bacteria. transformed into excessive, untargeted, persistent generation pro-oxidant free radicals (oxidative stress). normal neural transmission modified undirected, chronic low-level excitatory activity. Each characterized occurrence continuous inefficient diffused. signal/noise ratio several critical thus reduced beneficial responses replaced their impaired variants.

Language: Английский

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Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging

The EMBO Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 4, 2024

Abstract Mitophagy neutralizes mitochondrial damage, thereby preventing cellular dysfunction and apoptosis. Defects in mitophagy have been strongly implicated age-related neurodegenerative disorders such as Parkinson’s Alzheimer’s disease. While decreases throughout the lifespan of short-lived model organisms, it remains unknown whether a decline occurs aging mammalian brain—a question fundamental importance for understanding cell type- region-specific susceptibility to neurodegeneration. Here, we define longitudinal dynamics basal macroautophagy across neuronal non-neuronal types within intact mouse brain vivo. Quantitative profiling reporter cohorts from young geriatric ages reveals cell- tissue-specific alterations between distinct subregions populations, including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia interneurons. We also find that healthy is hallmarked by dynamic accumulation differentially acidified lysosomes several neural subsets. Our findings argue against any widespread mitophagic activity, instead demonstrating fluctuations trajectory, with strong implications ongoing theragnostic development.

Language: Английский

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Parkin, a Parkinson's disease-associated protein, mediates the mitophagy that plays a vital role in the pathophysiology of major depressive disorder

Neurochemistry International, Journal Year: 2024, Volume and Issue: 179, P. 105808 - 105808

Published: July 22, 2024

Language: Английский

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Harnessing Mitophagy for Therapeutic Advances in Aging and Chronic Neurodegenerative Diseases

Neuroglia, Journal Year: 2024, Volume and Issue: 5(4), P. 391 - 409

Published: Oct. 15, 2024

Introduction: Mitophagy, the selective degradation of damaged mitochondria, is essential for maintaining cellular health and function, particularly in high-energy demanding post-mitotic cells like neurons microglial cells. Aging results impaired mitophagy, leading to mitochondrial dysfunction, oxidative stress, release damage-associated proteins (DAMPs), neuroinflammation, which contribute neurodegenerative diseases such as Alzheimer’s Parkinson’s. Mitochondrial dysfunction also contributes pathophysiology depression by affecting synaptic plasticity, increasing heightening stress. Aim: In this review, we summarize recent developments on mechanisms its therapeutic role neuroprotection, implications aging complemented future research requirements implications. Result/Discussion: Therapeutic strategies that promote health, including enhancing mitophagy biogenesis, show promise treating depression. Recent findings have emphasized modulate pharmacological agents urolithin A rapamycin, genetic interventions PINK1/Parkin gene therapy, transplantation, lifestyle dietary caloric restriction, exercise, supplements resveratrol CoQ10. Key regulators pathway various BNIP3, NIX, FUNDC1, facilitate removal play a crucial role. Conclusions: These highlight importance understanding interplay between neuroinflammation modulation can reduce stress improve neuroinflammatory outcomes age-related diseases. However, despite significant progress, challenges remain underlying molecular regulation disorders.

Language: Английский

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Age‐specific and compartment‐dependent changes in mitochondrial homeostasis and cytoplasmic viscosity in mouse peripheral neurons

Aging Cell, Journal Year: 2024, Volume and Issue: unknown

Published: June 17, 2024

Abstract Mitochondria are dynamic bioenergetic hubs that become compromised with age. In neurons, declining mitochondrial axonal transport has been associated reduced cellular health. However, it is still unclear to what extent the decline of and function observed during ageing coupled, if somal mitochondria display compartment‐specific features make them more susceptible process. It also not known whether biophysical state cytoplasm, thought affect many functions, changes age impact trafficking homeostasis. Focusing on mouse peripheral nervous system, we show age‐dependent in accompanied by reduction membrane potential intramitochondrial viscosity, but calcium buffering, both mitochondria. Intriguingly, observe a specific increase cytoplasmic viscosity neuronal cell body, where most polarised, which correlates decreased diffusiveness. Increasing crowding somatic compartment DRG neurons grown microfluidic chambers reduces trafficking, suggesting mechanistic link between regulation dynamics. Our work provides reference for studying relationship homeostasis viscoelasticity cytoplasm compartment‐dependent manner ageing.

Language: Английский

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Mitophagy and long-term neuronal homeostasis

Journal of Cell Science, Journal Year: 2023, Volume and Issue: 136(11)

Published: June 1, 2023

ABSTRACT Neurons are highly polarized, post-mitotic cells that characterized by unique morphological diversity and complexity. As differentiated need to survive throughout organismal lifespan, neurons face exceptional energy challenges in time space. Therefore, heavily dependent on a healthy mitochondrial network for their proper function maintenance under both physiological stress conditions. Multiple quality control systems have evolved fine-tune number quality, thus preserving neuronal homeostasis. Here, we review the contribution of mitophagy, selective form autophagy targets dysfunctional or superfluous mitochondria degradation, maintaining nervous system In addition, discuss recent evidence implicating defective dysregulated mitophagy pathogenesis neurodegenerative diseases.

Language: Английский

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iPLA2β loss leads to age-related cognitive decline and neuroinflammation by disrupting neuronal mitophagy

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Sept. 18, 2024

Language: Английский

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Reduced Autophagy in Aged Trigeminal Neurons Causes Amyloid β Diffusion

Journal of Dental Research, Journal Year: 2023, Volume and Issue: 102(8), P. 938 - 946

Published: March 15, 2023

The relationship between oral health and the development of Alzheimer’s disease (AD) in elderly is not yet well understood. In this regard, association aging or neurodegeneration trigeminal nervous system accumulation amyloid-β(1–42) (Aβ 42 ) oligomers pathogenesis AD unknown. We focused on selective autophagy mesencephalic nucleus (Vmes) diffusion Aβ with respect to whether degeneration Vmes neurons affects oligomers. used female 2- 8-mo-old transgenic 3xTg-AD mice App NL-G-F knock-in immunohistochemically examined aging-related changes oligomer processing Vmes, which exhibits high amyloid-β (Aβ) expression. induced by extracting maxillary molars kinetics. Autophagosome-like membranes, stained positive for Aβ, HO-1, LC3B, were observed mice, while there was weak immunoreactivity membranes intraneuronal mice. By contrast, strong immunopositivity extracellular formation clusters expression Rubicon, indicates age-related deterioration autophagy, increased age neurons. Tooth extraction These results suggest that maintains homeostasis due leads into space possibly AD.

Language: Английский

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