Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation DOI Open Access
Kelsey R. Baron, Samantha Oviedo,

Sophia Krasny

et al.

Published: Sept. 25, 2024

Excessive mitochondrial fragmentation is associated with the pathologic dysfunction implicated in pathogenesis of etiologically-diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) – comprising four eIF2α kinases PERK, GCN2, PKR, and HRI a prominent stress-responsive signaling pathway that regulates morphology function to diverse types insult. This suggests pharmacologic, stress-independent activation ISR represents potential strategy mitigate human disease. Here, we show or GCN2 promotes adaptive elongation prevents induced by calcium ionophore ionomycin. Further, these reduces restores basal patient fibroblasts expressing pathogenic D414V variant pro-fusion GTPase MFN2 neurological dysfunctions ataxia, optic atrophy, sensorineural hearing loss. These results identify as prevent disease-relevant chemical genetic insults, further motivating pursuit highly selective kinase-activating compounds therapeutic diseases.

Language: Английский

Ventilator‐induced diaphragm dysfunction: phenomenology and mechanism(s) of pathogenesis DOI Open Access
Scott K. Powers

The Journal of Physiology, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 31, 2024

Abstract Mechanical ventilation (MV) is used to support and pulmonary gas exchange in patients during critical illness surgery. Although MV a life‐saving intervention for respiratory failure, an unintended side‐effect of the rapid development diaphragmatic atrophy contractile dysfunction. This MV‐induced weakness labelled as ‘ventilator‐induced diaphragm dysfunction’ (VIDD). VIDD important clinical problem because risk factor failure wean from MV. Indeed, inability remove ventilator results prolonged hospitalization increased morbidity mortality. The pathogenesis has been extensively investigated, revealing that mitochondrial production reactive oxygen species within muscle fibres promotes cascade redox‐regulated signalling events leading both accelerated proteolysis depressed protein synthesis. Together, these promote review highlights changes structure/function discusses cell‐signalling mechanisms responsible VIDD. report concludes with discussion potential therapeutic opportunities prevent suggestions future research this exciting field. image

Language: Английский

Citations

1
The Effects of Astaxanthin on Metabolic Syndrome: A Comprehensive Review DOI Creative Commons

Chunhao Gao,

Ni Gong,

Fangtian Chen

et al.

Marine Drugs, Journal Year: 2024, Volume and Issue: 23(1), P. 9 - 9

Published: Dec. 27, 2024

Metabolic syndrome (MS) represents a complex cluster of metabolic disorders primarily characterized by obesity, insulin resistance, hyperglycemia, dyslipidemia, hypertension, and hyperuricemia. Diet functional ingredients play pivotal role in seeking non-pharmacological strategies to prevent ameliorate MS. Astaxanthin (AST), carotenoid found various marine organisms, exhibits exceptional antioxidant properties holds great promise as natural compound that improves This article introduces the basic AST, including its absorptance pathways, along with isomers. Most importantly, we comprehensively review effects mechanisms AST on improving primary components These involve regulating signal transduction, transport, or pathways within body, well influencing intestinal microbiota metabolites, thereby exerting positive metabolism inhibiting occurrence emphasizes potential efficacy managing However, more studies are needed confirm clinical effect MS reveal molecular mechanisms.

Language: Английский

Citations

1
Dose-Dependent Effects of Radiation on Mitochondrial Morphology and Clonogenic Cell Survival in Human Microvascular Endothelial Cells DOI Creative Commons
Li Wang,

Rafael Rivas,

Angelo Wilson

et al.

Cells, Journal Year: 2023, Volume and Issue: 13(1), P. 39 - 39

Published: Dec. 23, 2023

To better understand radiation-induced organ dysfunction at both high and low doses, it is critical to how endothelial cells (ECs) respond radiation. The impact of irradiation (IR) on ECs varies depending the dose administered. High doses can directly damage ECs, leading EC impairment. In contrast, effects are subtle but more complex. Low in this study refer radiation exposure levels that below those cause immediate necrotic damage. Mitochondria primary cellular components affected by IR, explored their role determining effect microvascular cells. Human dermal (HMEC-1) were exposed varying IR ranging from 0.1 Gy 8 (~0.4 Gy/min) AFRRI 60-Cobalt facility. Results indicated led a dose-dependent reduction cell survival, which be attributed factors such as DNA damage, oxidative stress, senescence, mitochondrial dysfunction. However, induced small significant increase was achieved without detectable or HMEC-1. Moreover, morphology assessed, revealing all increased percentage elongated mitochondria, with (0.25 0.5 Gy) having greater than doses. only caused an fragmentation/swelling. further revealed elongation, likely via fusion protein 1 (Mfn1), while fragmentation decrease optic atrophy (Opa1). conclusion, suggests, for first time, changes involved mechanism survival This research, delineating specific mechanisms through affects cells, offers invaluable insights into potential cardiovascular health.

Language: Английский

Citations

3
Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation DOI Creative Commons
Kelsey R. Baron, Samantha Oviedo,

Sophia Krasny

et al.

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

Published: June 10, 2024

SUMMARY Excessive mitochondrial fragmentation is associated with the pathologic dysfunction implicated in pathogenesis of etiologically-diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) – comprising four eIF2α kinases PERK, GCN2, PKR, and HRI a prominent stress-responsive signaling pathway that regulates morphology function to diverse types insult. This suggests pharmacologic activation ISR represents potential strategy mitigate human disease. Here, we show or GCN2 promotes adaptive elongation prevents induced by calcium ionophore ionomycin. Further, reduces restores basal patient fibroblasts expressing pathogenic D414V variant pro-fusion GTPase MFN2 neurological dysfunctions ataxia, optic atrophy, sensorineural hearing loss. These results identify as prevent disease-relevant chemical genetic insults, further motivating pursuit highly selective kinase-activating compounds therapeutic diseases.

Language: Английский

Citations

0
Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation DOI Open Access
Kelsey R. Baron, Samantha Oviedo,

Sophia Krasny

et al.

Published: Sept. 25, 2024

Excessive mitochondrial fragmentation is associated with the pathologic dysfunction implicated in pathogenesis of etiologically-diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) – comprising four eIF2α kinases PERK, GCN2, PKR, and HRI a prominent stress-responsive signaling pathway that regulates morphology function to diverse types insult. This suggests pharmacologic, stress-independent activation ISR represents potential strategy mitigate human disease. Here, we show or GCN2 promotes adaptive elongation prevents induced by calcium ionophore ionomycin. Further, these reduces restores basal patient fibroblasts expressing pathogenic D414V variant pro-fusion GTPase MFN2 neurological dysfunctions ataxia, optic atrophy, sensorineural hearing loss. These results identify as prevent disease-relevant chemical genetic insults, further motivating pursuit highly selective kinase-activating compounds therapeutic diseases.

Language: Английский

Citations

0