The Role of Endothelial Cell Mitophagy in Age-Related Cardiovascular Diseases

Aging and Disease, Journal Year: 2024, Volume and Issue: unknown, P. 0 - 0

Published: Jan. 1, 2024

Aging is a major risk factor for cardiovascular diseases (CVD), and mitochondrial autophagy impairment considered significant physiological change associated with aging. Endothelial cells play crucial role in maintaining vascular homeostasis function, participating various processes such as regulating tone, coagulation, angiogenesis, inflammatory responses. As aging progresses, endothelial worsens, leading to the development of numerous diseases. Therefore, vital preventing treating age-related However, there currently lack systematic reviews this area. To address gap, we have written review provide new research therapeutic strategies managing

Language: Английский

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Cell life-or-death events in osteoporosis: All roads lead to mitochondrial dynamics

Pharmacological Research, Journal Year: 2024, Volume and Issue: 208, P. 107383 - 107383

Published: Aug. 28, 2024

Mitochondria exhibit heterogeneous shapes and networks within among cell types tissues, also in normal or osteoporotic bone tissues with complex types. This dynamic characteristic is determined by the high plasticity provided mitochondrial dynamics stemmed from responding to survival functional requirements of various cells a specific microenvironments. In contrast, dysfunction, induced dysregulation dynamics, may act as trigger death signals, including common apoptosis other forms programmed (PCD). These PCD processes consisting tightly structured cascade gene expression events, can further influence remodeling facilitating cells. Mitochondrial therefore, drive stand at crossroads life integrating external signals altering metabolism, shape, signal-response properties mitochondria. implies that targeting displays significant potential treatment osteoporosis. Considerable effort has been made osteoporosis emphasize parallel roles mitochondria regulating energy calcium signal transduction, oxidative stress, inflammation, death. However, emerging field dynamics-related not well understood. Herein, bridge gap, we outline latest knowledge on during

Language: Английский

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OPA1 deficiency induces mitophagy through PINK1/Parkin pathway during bovine oocytes maturation

Theriogenology, Journal Year: 2024, Volume and Issue: 234, P. 51 - 63

Published: Dec. 4, 2024

Language: Английский

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Loss of PTPN21 disrupted mitochondrial metabolic homeostasis and aggravated experimental pulmonary fibrosis

Respiratory Research, Journal Year: 2024, Volume and Issue: 25(1)

Published: Dec. 4, 2024

Idiopathic pulmonary fibrosis (IPF) is a high-mortality lung disease with unclear pathogenesis. Convincing evidence suggests that an imbalance in mitochondrial homeostasis resulting from repeated injury to alveolar epithelial type 2 cells (AEC2) underlies IPF. Non-receptor protein tyrosine phosphatase 21 (PTPN21) performs various functions cancer; however, its role IPF has not been studied. This study aimed investigate the of PTPN21 fibrosis. The experimental results showed loss exacerbated by increasing cell numbers bronchoalveolar lavage fluid, hydroxyproline content, and extracellular matrix expression fibronectin α-smooth muscle actin (α-SMA) bleomycin-challenged mouse lungs. In A549 (AEC2), knockdown suppressed focal adhesion migration, reduced fission increased fusion, level superoxide, decreased membrane potential ATP levels. Simultaneously, impaired autophagy, intracellular reactive oxygen species Treatment fibroblasts (MRC-5) primary human (PHLF)) supernatant PTPN21-knockdown fibronectin, collagen 1 α-SMA. Conversely, overexpression produced opposite effects. However, treatment MRC-5 PHLF PTPN21-overexpressing only slightly cells, but did change summary, this revealed disrupted metabolic homeostasis, leading inactivation deposition proteins fibroblasts, thereby exacerbating

Language: Английский

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LC3A-mediated autophagy elicits PERK-eIF2α-ATF4 axis activation and mitochondrial dysfunction: Exposing vulnerability in aggresome positive cancer cells

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(6), P. 107398 - 107398

Published: May 20, 2024

The unfolded protein response pathways (UPR), autophagy, and compartmentalization of misfolded proteins into inclusion bodies are critical components the quality control network. Among bodies, aggresomes particularly intriguing due to their association with cellular survival, drug resistance, aggresive cancer behavior. Aggresomes molecular condensates formed when collapsed vimentin cages encircle before final removal by autophagy. Yet significant gaps persist in mechanisms governing aggresome formation elimination cells. Understanding these is crucial, especially considering involvement LC3A, a member MAP1LC3 family, which plays unique role autophagy regulation has been reported be epigenetically silenced many cancers. Herein, we utilized tetracycline-inducible expression LC3A investigate its choroid plexus carcinoma cells, inherently exhibit presence aggresomes. Live cell imaging was employed demonstrate effect on aggresome-positive while SILAC-based proteomics identified LC3A-induced pathway alterations. Our findings demonstrated that extended associated senescence. However, obstruction lysosomal degradation this context deleterious viability. In observed alterations mitochondrial morphology, reflected dysfunction increased ROS production. Furthermore, elicited activation PERK-eIF2α-ATF4 axis UPR, underscoring change conclusion, our results elucidate LC3A-mediated alters network, exposing vulnerability

Language: Английский

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LDL exposure disrupts mitochondrial function and dynamics in a hippocampal neuronal cell line

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 12, 2024

ABSTRACT Hypercholesterolemia has been associated with cognitive dysfunction and neurodegenerative disease. Moreover, this metabolic condition disrupts the blood-brain barrier, allowing Low-Density Lipoprotein (LDL) to enter Central Nervous System. Thus, we investigated effects of LDL exposure on mitochondrial function in a mouse hippocampal neuronal cell line (HT-22). HT-22 cells were exposed human (50 300 μg/mL) for 24 hours. After this, intracellular lipid droplet (LD) content, viability, death, parameters performed. We found that higher concentration increases LD content compared control. Both concentrations increased number Annexin V-positive cells, indicating apoptosis. parameters, leads decrease complexes I II both tested reduction Mitotracker™ Red fluorescence Green ratio concentration, mitochondria. The incubation induces superoxide production dismutase activity lower cells. Finally, exhibit an increase expression genes fusion (OPA1 Mitofusin 2) concentration. In conclusion, our findings suggest modulation dynamics

Language: Английский

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LDL Exposure Disrupts Mitochondrial Function and Dynamics in a Hippocampal Neuronal Cell Line

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 20, 2024

Language: Английский

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De novo missense variants in the PP2A regulatory subunit PPP2R2B in a neurodevelopmental syndrome: potential links to mitochondrial dynamics and spinocerebellar ataxias

Human Molecular Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 20, 2024

Abstract The heterotrimeric protein phosphatase 2A (PP2A) complex catalyzes about half of Ser/Thr dephosphorylations in eukaryotic cells. A CAG repeat expansion the neuron-specific PP2A regulatory subunit PPP2R2B gene causes spinocerebellar ataxia type 12 (SCA12). We established five monoallelic missense variants (four confirmed as de novo) a cause intellectual disability with developmental delay (R149P, T246K, N310K, E37K, I427T). In addition to moderate severe and delay, affected individuals presented seizures, microcephaly, aggression, hypotonia, well broad-based or stiff gait. used biochemical cellular assays, including novel luciferase complementation assay interrogate holoenzyme assembly activity, deregulated mitochondrial dynamics possible pathogenic mechanisms. Cell-based assays documented impaired ability incorporate into holoenzyme, localize mitochondria, induce fission neuronal dephosphorylate enzyme dynamin-related 1. AlphaMissense-based pathogenicity prediction suggested that an additional seven unreported may be pathogenic. conclusion, our studies identify loss-of-function at locus basis for syndromic delay. They also extend PPP2R2B-related pathologies from neurodegenerative (SCA12) neurodevelopmental disorders suggests altered contribute

Language: Английский

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NOTCH2NLC GGC intermediate repeat with serine induces hypermyelination and early Parkinson’s disease-like phenotypes in mice

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Nov. 28, 2024

Abstract Background The expansion of GGC repeats (typically exceeding 60 repeats) in the 5’ untranslated region (UTR) NOTCH2NLC gene (N2C) is linked to N2C-related repeat disorders (NREDs), such as neuronal intranuclear inclusion disease (NIID), frontotemporal dementia (FTD), essential tremor (ET), and Parkinson’s (PD). These share common clinical manifestations, including parkinsonism, dementia, seizures, muscle weakness. Intermediate sizes ranging from 40 repeats, particularly those with AGC-encoded serine insertions, have been reported be associated PD; however, functional implications these intermediate insertion remain unexplored. Methods Here, we utilized cellular models harbouring different N2C variant 2 (N2C2) CRISPR-Cas9 engineered transgenic mouse carrying N2C2 without elucidate underlying pathophysiology NREDs. Results Our findings revealed that (32G13S) led mitochondrial dysfunction cell death vitro. neurotoxicity was influenced by length exacerbated presence insertion. In 12-month-old mice, 32G13S intensified aggregation exhibited early PD-like characteristics, formation α-synuclein fibers midbrain loss tyrosine hydroxylase (TH)-positive neurons both cortex striatum. Additionally, induced hyperexcitability caused locomotor behavioural impairments. Transcriptomic analysis indicated dysregulation calcium signaling MAPK pathways, which are critical for function. Notably, genes myelin sheath components, MBP MOG , were dysregulated mouse. Further investigations using immunostaining transmission electron microscopy dysfunction-related hypermyelination cortex. Conclusions vitro vivo provide first evidence N2C-GGC promotes N2C, leading dysfunction-associated hyperexcitability. changes contribute motor deficits neurodegeneration

Language: Английский

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Apolipoprotein-L Functions in Membrane Remodeling

Cells, Journal Year: 2024, Volume and Issue: 13(24), P. 2115 - 2115

Published: Dec. 20, 2024

The mammalian Apolipoprotein-L families (APOLs) contain several isoforms of membrane-interacting proteins, some which are involved in the control membrane dynamics (traffic, fission and fusion). Specifically, human APOL1 APOL3 appear to remodeling linked pathogen infection. Through its association with Non-Muscular Myosin-2A (NM2A), controls Golgi-derived trafficking vesicles carrying lipid scramblase Autophagy-9A (ATG9A). These deliver together phosphatidylinositol-4-kinase-B (PI4KB) activated Stimulator Interferon Genes (STING) mitochondrion-endoplasmic reticulum (ER) contact sites (MERCSs) for induction completion mitophagy apoptosis. direct interactions PI4KB activity controllers (Neuronal Calcium Sensor-1, or NCS1, Calneuron-1, CALN1, ADP-Ribosylation Factor-1, ARF1), PI(4)P synthesis. is required different processes infection-induced inflammation: (i) STING activation at Golgi subsequent lysosomal degradation inflammation termination; (ii) mitochondrion MERCSs apoptosis; (iii) phagolysosome formation antigen processing. In addition, governs mitophagosome fusion endolysosomes completion, APOL3-like murine APOL7C phagosome permeabilization cross-presentation dendritic cells. Similarly, can induce intracellular bacterial membranes, a role also be proposed endothelial APOLd1 adipocyte mAPOL6, promote angiogenesis adipogenesis, respectively, under inflammatory conditions. Thus, APOL play distinct roles associated inflammation.

Language: Английский

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