Disturb mitochondrial associated proteostasis: Neurodegeneration and imperfect ageing

Frontiers in Cell and Developmental Biology, Год журнала: 2023, Номер 11

Опубликована: Март 10, 2023

The disturbance in mitochondrial functions and homeostasis are the major features of neuron degenerative conditions, like Parkinson’s disease, Amyotrophic Lateral Sclerosis, Alzheimer’s along with protein misfolding. aberrantly folded proteins known to link impaired pathways, further contributing disease pathogenesis. Despite their central significance, implications disruption on other organelles cellular processes remain insufficiently explored. Here, we have reviewed dysfunction physiology, under degenerating conditions. misfolded impact quality control mechanisms mitochondria, such as fission, fusion, mitophagy, proteasomal clearance, detriment neuron. adversely affected functional roles, oxidative phosphorylation, calcium homeostasis, biomolecule synthesis well its axes contacts endoplasmic reticulum lysosomes also discussed. Mitochondria sense respond multiple cytotoxic stress make cell adapt survive, though chronic leads death. can be candidates for biomarkers therapeutic targets. Investigation internetworking between mitochondria neurodegeneration enhance our holistic understanding conditions help designing more targeted therapies.

Язык: Английский

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NTRK1 knockdown induces mouse cognitive impairment and hippocampal neuronal damage through mitophagy suppression via inactivating the AMPK/ULK1/FUNDC1 pathway

Cell Death Discovery, Год журнала: 2023, Номер 9(1)

Опубликована: Окт. 31, 2023

Abstract Hippocampal neuronal damage may induce cognitive impairment. Neurotrophic tyrosine kinase receptor 1 (NTRK1) reportedly regulates damage, although the underlying mechanism remains unclear. The present study aimed to investigate role of NTRK1 in mouse hippocampal and specific mechanism. A NTRK1-knockdown model was established subjected pre-treatment with BAY-3827, followed by a behavioral test, Nissl staining, NeuN immunofluorescence (IF) staining evaluate impairment damage. Next, an vitro analysis conducted using CCK-8 assay, TUNEL IF DCFH-DA JC-1 ATP content mRFP-eGFP-LC3 LC3-II elucidate effect on activity, apoptosis, mitochondrial function, autophagy. Subsequently, rescue experiments were performed subjecting neurons O304 Rapamycin. AMPK/ULK1/FUNDC1 pathway activity mitophagy detected western blotting (WB) analysis. Resultantly, vivo revealed that knockdown induced tissue addition inactivating tissues mice. treatment BAY-3827 exacerbated depressive-like behavior knockdown. results indicated attenuated viability, expression, production, membrane potential, mitophagy, while enhancing apoptosis ROS production neurons. Conversely, rapamycin abrogated suppression promotion upon silencing. Conclusively, induces through via pathway. This finding would provide insight leading development novel strategies for due

Язык: Английский

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Transfer and fates of damaged mitochondria: role in health and disease

FEBS Journal, Год журнала: 2024, Номер unknown

Опубликована: Март 28, 2024

Intercellular communication is pivotal in mediating the transfer of mitochondria from donor to recipient cells. This process orchestrates various biological functions, including tissue repair, cell proliferation, differentiation and cancer invasion. Typically, dysfunctional depolarized are eliminated through intracellular or extracellular pathways. Nevertheless, increasing evidence suggests that intercellular damaged associated with pathogenesis diverse diseases. review investigates prevalent triggers mitochondrial damage underlying mechanisms transfer, elucidates role directional both physiological pathological contexts. Additionally, we propose potential previously unknown explore their prospective roles disease prevention therapy.

Язык: Английский

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Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites

Frontiers in Neuroscience, Год журнала: 2022, Номер 16

Опубликована: Июнь 21, 2022

Neurodegenerative diseases (NDs) are generally considered proteinopathies but whereas this may initiate disease in familial cases, onset sporadic originate from a gradually disrupted organellar homeostasis. Herein, endolysosomal abnormalities, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and altered lipid metabolism commonly observed early preclinical stages of major NDs, including Parkinson's (PD) Alzheimer's (AD). Among the multitude underlying defective molecular mechanisms that have been suggested past decades, dysregulation inter-organellar communication through so-called membrane contact sites (MCSs) is becoming increasingly apparent. Although MCSs exist between almost every other type subcellular organelle, to date, most focus has put on ER mitochondria given these compartments critical neuronal survival. Contributions MCSs, notably those with endolysosomes droplets emerging, supported as well by genetic studies, identifying genes functionally involved lysosomal In review, we summarize identity organelle interactome yeast mammalian cells, critically evaluate evidence supporting contribution disturbed general homeostasis taking PD AD examples.

Язык: Английский

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Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics

The Journal of Cell Biology, Год журнала: 2022, Номер 221(10)

Опубликована: Авг. 31, 2022

Lysosomes are highly dynamic organelles implicated in multiple diseases. Using live super-resolution microscopy, we found that lysosomal tethering events rarely undergo fusion, but rather untether over time to reorganize the network. Inter-lysosomal untethering driven by a mitochondrial Mid51/Fis1 complex undergoes coupled oligomerization on outer membrane. Importantly, Fis1 mediates TBC1D15 (Rab7-GAP) recruitment drive inter-lysosomal via Rab7 GTP hydrolysis. Moreover, inhibiting either mutant or Mid51 potentially associated with Parkinson’s disease prevents events, resulting misregulated network dynamics. In contrast, dominant optic atrophy–linked Mid51, which does not inhibit oligomerization, disrupt downstream As conversely also regulates our work further highlights an oligomeric mechanistically couples together both Drp1 and hydrolysis machinery at mitochondria–lysosome contact sites. These findings have significant implications for organelle networks cellular homeostasis human disease.

Язык: Английский

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Inter-Organelle Contact Sites Mediate the Intracellular Antioxidant Activity of Platinum Nanozymes: A New Perspective on Cell–Nanoparticle Interaction and Signaling

ACS Applied Materials & Interfaces, Год журнала: 2023, Номер 15(3), С. 3882 - 3893

Опубликована: Янв. 11, 2023

The catalytic and antioxidant properties of platinum nanoparticles (PtNPs) make them promising candidates for several applications in nanomedicine. However, an open issue, still shared among most nanomaterials, is the understanding on how internalized PtNPs, which are confined within endo-lysosomal compartments, can exert their activities. To address this problem, here we study protective effect 5 nm PtNPs a human hepatic (HepG2) cell line exposed to dichlorodiphenylethylene (DDE) as model oxidative stress. Our results indicate that very efficient reduce DDE-induced damage HepG2 cells, extent depends DDE dose. contrast unbalance mitochondrial dynamics induced by increase expression SOD2 enzyme recovers cells from Interestingly, treated with PtNPs─alone or combination DDE─mitochondria form contact sites rough endoplasmic reticulum endo-lysosomes containing nanoparticles. These findings capability through intrinsic modulating functionality, mediated inter-organelle crosstalk. This sheds new light about action mechanisms discloses novel nano-biointeraction mechanism at intracellular level, modulated communication signaling.

Язык: Английский

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Common genetic risk for Parkinson's disease and dysfunction of the endo-lysosomal system

Philosophical Transactions of the Royal Society B Biological Sciences, Год журнала: 2024, Номер 379(1899)

Опубликована: Фев. 19, 2024

Parkinson's disease is a progressive neurological disorder, characterized by prominent movement dysfunction. The past two decades have seen rapid expansion of our understanding the genetic basis Parkinson's, initially through identification monogenic forms and, more recently, genome-wide association studies identifying common risk variants. Intriguingly, number cellular pathways emerged from these analysis as playing central roles in aetiopathogenesis Parkinson's. In this review, impact data deriving analyses for upon functional will be examined, with particular focus on examples endo-lysosomal and mitochondrial challenges moving to variants discussed, final consideration current state architecture disorder. This article part discussion meeting issue ‘Understanding network neurodegeneration’.

Язык: Английский

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A SPLICS reporter reveals $${{{{{\boldsymbol{\alpha }}}}}}$$-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 19, 2024

Abstract Mitochondrial and lysosomal activities are crucial to maintain cellular homeostasis: optimal coordination is achieved at their membrane contact sites where distinct protein machineries regulate organelle network dynamics, ions metabolites exchange. Here we describe a genetically encoded SPLICS reporter for short- long- juxtapositions between mitochondria lysosomes. We report the existence of narrow wide lysosome-mitochondria contacts differently modulated by mitophagy, autophagy genetic manipulation tethering factors. The overexpression α-synuclein (α-syn) reduces apposition mitochondria/lysosomes membranes affects privileged Ca 2+ transfer, impinging on TFEB nuclear translocation. observe enhanced translocation in α-syn-overexpressing cells. propose that α-syn, interfering with impacts local regulated pathways, among which mediated signaling, turn mitochondrial function. Defects lysosome represent common hallmark neurodegenerative diseases: targeting communication could open therapeutic avenues.

Язык: Английский

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Mitochondrial dysfunction in the pathophysiology of renal diseases

AJP Renal Physiology, Год журнала: 2024, Номер 326(5), С. F768 - F779

Опубликована: Март 7, 2024

Mitochondria are essential organelles in the human body, serving as metabolic factory of whole organism. When mitochondria dysfunctional, it can affect all organs body. The kidney is rich mitochondria, and its function closely related to development diseases. Studying relationship between disease progression great interest. In past decade, scientists have made inspiring progress investigating role pathophysiology renal This article discusses various mechanisms for maintaining mitochondrial quality, including energetics, biogenesis, dynamics, DNA repair, proteolysis unfolded protein response, autophagy, mitochondria-derived vesicles, mitocytosis. also highlights cross talk other organelles, with a focus on Finally, concludes an overview mitochondria-related clinical research.

Язык: Английский

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The Bis(monoacylglycero)-phosphate Hypothesis: From Lysosomal Function to Therapeutic Avenues

Annual Review of Biochemistry, Год журнала: 2024, Номер 93(1), С. 447 - 469

Опубликована: Апрель 11, 2024

Lysosomes catabolize and recycle lipids other biological molecules to maintain cellular homeostasis in diverse nutrient environments. Lysosomal lipid catabolism relies on the stimulatory activity of bis(monoacylglycero)phosphate (BMP), an enigmatic whose levels are altered across myriad lysosome-associated diseases. Here, we review discovery BMP over half a century ago its structural properties that facilitate activation hydrolases recruitment their coactivators. We further discuss current, yet incomplete, understanding anabolism. To conclude, role diseases potential for modulating by pharmacologically activating inhibiting synthase therapeutically target lysosomal storage disorders, drug-induced phospholipidosis, Alzheimer's disease, Parkinson's frontotemporal dementia, cancer, viral infection.

Язык: Английский

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