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

Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight DOI Creative Commons
Franklyn Nonso Iheagwam,

A B Joseph,

Eniola Deborah Adedoyin

et al.

Pathophysiology, Journal Year: 2025, Volume and Issue: 32(1), P. 9 - 9

Published: Feb. 13, 2025

Diabetes mellitus represents a complicated metabolic condition marked by ongoing hyperglycemia arising from impaired insulin secretion, inadequate action, or combination of both. Mitochondrial dysfunction has emerged as significant contributor to the aetiology diabetes, affecting various processes critical for glucose homeostasis. This review aims elucidate complex link between mitochondrial and covering spectrum diabetes types, role mitochondria in resistance, highlighting pathophysiological mechanisms, DNA damage, altered biogenesis dynamics. Additionally, it discusses clinical implications complications its complications, diagnostic approaches assessing function diabetics, therapeutic strategies, future directions, research opportunities.

Language: Английский

Citations

0
Unraveling the Mystery of Insulin Resistance: From Principle Mechanistic Insights and Consequences to Therapeutic Interventions DOI Open Access
Rashid Mir, Mohammed Jeelani, Muffarah Hamid Alharthi

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(6), P. 2770 - 2770

Published: March 19, 2025

Insulin resistance (IR) is a significant factor in the development and progression of metabolic-related diseases like dyslipidemia, T2DM, hypertension, nonalcoholic fatty liver disease, cardiovascular cerebrovascular disorders, cancer. The pathogenesis IR depends on multiple factors, including age, genetic predisposition, obesity, oxidative stress, among others. Abnormalities insulin-signaling cascade lead to host, insulin receptor abnormalities, internal environment disturbances, metabolic alterations muscle, liver, cellular organelles. complex multifaceted characteristics signaling envisage their thorough comprehensive understanding at molecular level. Therapeutic strategies for include exercise, dietary interventions, pharmacotherapy. However, there are still gaps be addressed, more precise biomarkers associated chronic lifestyle interventions needed. Understanding these pathways essential developing effective treatments IR, reducing healthcare costs, improving quality patient life.

Language: Английский

Citations

0
Integrated analyses revealed the potential role and immune link of mitochondrial dysfunction between periodontitis and type 2 diabetes mellitus DOI

Shengyuan Pan,

Lanxin Yang, Wenjie Zhong

et al.

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 130, P. 111796 - 111796

Published: March 1, 2024

Language: Английский

Citations

3
Comprehensive Analysis of Novel Synergistic Antioxidant Formulations: Insights into Pharmacotechnical, Physical, Chemical, and Antioxidant Properties DOI Creative Commons

Sorinel Marius Neacșu,

Magdalena Mititelu,

Emma Adriana Ozon

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(6), P. 690 - 690

Published: May 27, 2024

(1) Background: Oxidative stress plays a pivotal role in the pathogenesis of various diseases, including neurodegenerative disorders, cardiovascular cancer, and diabetes, highlighting pressing need for effective antioxidant interventions. (2) Methods: In this study, we aimed to develop characterise two novel formulations, F3 F4, as therapeutic interventions oxidative stress-related conditions. (3) Results: The physicochemical characterisation, preformulation analysis, formulation, preparation filling powders capsules, capsule content evaluation, activity assessment formulations were assessed. These comprise combination well-established antioxidants like quercetin, biotin, coenzyme Q10, resveratrol. Through comprehensive testing, formulations' efficacy, stability, potential synergistic interactions evaluated. (4) Conclusions: findings underscore promising these disorders highlight significance mitigating their progression.

Language: Английский

Citations

3
Human Aging and Age-Related Diseases: From Underlying Mechanisms to Pro-Longevity Interventions DOI Creative Commons
Piotr Paweł Chmielewski, Krzysztof Data, Bartłomiej Strzelec

et al.

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

Published: Jan. 1, 2024

As human life expectancy continues to rise, becoming a pressing global concern, it brings into focus the underlying mechanisms of aging. The increasing lifespan has led growing elderly population grappling with age-related diseases (ARDs), which strains healthcare systems and economies worldwide. While senescence was once regarded as an immutable inexorable phenomenon, impervious interventions, emerging field geroscience now offers innovative approaches aging, holding promise extending period healthspan in humans. Understanding intricate links between aging pathologies is essential addressing challenges presented by populations. A substantial body evidence indicates shared pathways contributing development progression various ARDs. Consequently, novel interventions targeting intrinsic have potential delay onset diverse pathological conditions, thereby healthspan. In this narrative review, we discuss most promising methods aimed at modulating harbor mitigate ARDs future. We also outline complexity review recent empirical identify rational strategies for promoting healthy

Language: Английский

Citations

2
Pectolinarigenin Improves Oxidative Stress and Apoptosis in Mouse NSC-34 Motor Neuron Cell Lines Induced by C9-ALS-Associated Proline–Arginine Dipeptide Repeat Proteins by Enhancing Mitochondrial Fusion Mediated via the SIRT3/OPA1 Axis DOI Creative Commons
Ru‐Huei Fu

Antioxidants, Journal Year: 2023, Volume and Issue: 12(11), P. 2008 - 2008

Published: Nov. 16, 2023

Amyotrophic lateral sclerosis (ALS) is considered a fatal progressive degeneration of motor neurons (MN) caused by oxidative stress and mitochondrial dysfunction. There are currently no treatments available. The most common inherited form ALS the C9orf72 mutation (C9-ALS). proline-arginine dipeptide repeat protein (PR-DPR) produced C9-ALS has been confirmed to be functionally acquired pathogenic factor that can cause increased ROS, defects, apoptosis in neurons. Pectolinarigenin (PLG) from traditional medicinal herb Linaria vulgaris antioxidant anti-apoptotic properties. I established mouse NSC-34 neuron cell line model expressing PR-DPR neuroprotective effect PLG. results showed ROS production could improved PLG treatment. In terms mechanism research, inhibited activity fusion proteins OPA1 mitofusin 2. Conversely, expression fission 1 dynamin-related (DRP1) increased. However, treatment reversed these effects. Furthermore, found deacetylation OPA1. Deacetylation enhances resistance apoptosis. Finally, transfection with Sirt3 small interfering RNA abolished effects summary, which alleviates toxicity mainly achieved activating SIRT3/OPA1 axis regulate balance dynamics. Taken together, potential preclinical studies for drug development deserves further evaluation.

Language: Английский

Citations

6
Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells DOI Open Access
Manivannan Yegambaram,

Xutong Sun,

Alejandro Garcia Flores

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(24), P. 17533 - 17533

Published: Dec. 15, 2023

The disruption of mitochondrial dynamics has been identified in cardiovascular diseases, including pulmonary hypertension (PH), ischemia-reperfusion injury, heart failure, and cardiomyopathy. Mitofusin 2 (Mfn2) is abundantly expressed vasculature cells at the outer membrane to modulate fusion. Previously, we have reported reduced levels Mfn2 fragmented mitochondria arterial endothelial (PAECs) isolated from a sheep model PH induced by over-circulation restoring normalized function. In this study, assessed effect increased expression on metabolism, bioenergetics, reactive oxygen species production, potential control PAECs. Using an adenoviral system overexpress PAECs utilizing 13C labeled substrates, TCA cycle metabolites. We pyruvate lactate production cells, revealing glycolytic phenotype (Warburg phenotype). overexpression decreased ATP rate, rate disrupted bioenergetics. increase glycolysis was linked hypoxia-inducible factor 1α (HIF-1α) protein levels, elevated (mt-ROS), potential. Our data suggest that disrupting fusion/fission balance favor hyperfusion leads metabolic shift promotes aerobic glycolysis. Thus, therapies designed fusion should be approached with caution.

Language: Английский

Citations

4
Thinned young apple powder prevents obesity-induced neuronal apoptosis via improving mitochondrial function of cerebral cortex in mice DOI
Jiacheng Fang, Peng Jiang, Xincen Wang

et al.

The Journal of Nutritional Biochemistry, Journal Year: 2024, Volume and Issue: 126, P. 109588 - 109588

Published: Jan. 22, 2024

Language: Английский

Citations

1
Resveratrol impinges on retrograde communication without inducing mitochondrial biogenesis in aged rat soleus muscle DOI Creative Commons
Rosa Di Lorenzo, Guglielmina Chimienti, Anna Picca

et al.

Experimental Gerontology, Journal Year: 2024, Volume and Issue: 194, P. 112485 - 112485

Published: June 13, 2024

The natural polyphenol resveratrol (RSV) might counteract the skeletal muscle age-related loss of mass and strength/function partly acting on mitochondria. This work analysed effects a six-week administration RSV (50 mg/kg/day) in oxidative Soleus (Sol) old rats (27 months old). key mitochondrial biogenesis proteins led to un unchanged amount SIRT1 protein marked decrease (60 %) PGC-1α protein. In addition, Peroxyredoxin 3 (PRXIII) decreased by 50 %, which overall suggested absence induction Sol. A novel direct correlation between PRXIII was demonstrated analysis ad-libitum (AL) rats, supporting reciprocally coordinated expression proteins. supplementation an unexpected % increase frequency oxidized base OH8dG mtDNA. Furthermore, induced DRP1 dynamics. both rat groups inverse as well were also found, suggestive relationship damage mtDNA activity. Such results may indicate that antioxidant activity aged Sol impinged fiber-specific, ROS-mediated, retrograde communication, thereby affecting SIRT1, PRXIII, reducing compensatory responses stress decline.

Language: Английский

Citations

1
Modifications of Mitochondrial Network Morphology Affect the MAVS-Dependent Immune Response in L929 Murine Fibroblasts during Ectromelia Virus Infection DOI Creative Commons
Karolina P. Gregorczyk-Zboroch, Lidia Szulc‐Dąbrowska,

Pola Pruchniak

et al.

Pathogens, Journal Year: 2024, Volume and Issue: 13(9), P. 717 - 717

Published: Aug. 23, 2024

Since smallpox vaccination was discontinued in 1980, there has been a resurgence of poxvirus infections, particularly the monkeypox virus. Without global recommendation to use vaccine, population is not immune, posing severe threat public health. Given these circumstances, it crucial understand relationship between poxviruses and their hosts. Therefore, this study focuses on ectromelia virus, causative agent mousepox, which serves as an excellent model for studying pathogenesis. Additionally, we investigated role mitochondria innate antiviral immunity during ECTV infection, focusing specifically mitochondrial signaling protein. The used Moscow strain L929 mouse fibroblasts. Cells were treated with chemical modulators network: Mdivi-1 CCCP. Our investigation revealed that elongated network attenuates suppression MAVS-dependent by reduces replication fibroblasts compared cells unaltered network. Conversely, fragmented number progeny virions while increasing inhibition virus-induced immune response infection. In conclusion, our showed modifications morphology alter ECTV-infected

Language: Английский

Citations

1