Exploring the Mechanism of Ferroptosis Induction by Sappanone A in Cancer: Insights into the Mitochondrial Dysfunction Mediated by NRF2/xCT/GPX4 Axis

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(13), P. 5145 - 5161

Published: Jan. 1, 2024

Non-small cell lung cancer (NSCLC), a major subtype of cancer, encompasses squamous carcinoma, adenocarcinoma, and large carcinoma. Compared to small NSCLC cells grow divide more slowly, their metastasis occurs at later stage. Currently, chemotherapy is the primary treatment for this disease. Sappanone A (SA) flavonoid compound extracted from plant Caesalpinia sappan, known its antitumor, redox-regulating, anti-inflammatory properties. Recent studies have investigated interaction SA with mitochondrial pathways in regulating death through Nrf-2/GPX-4/xCT axis. This study specifically explores mechanism by which affects morphology structure regulation mitophagy biogenesis tumor cells. The primarily utilizes second-generation transcriptomic sequencing data molecular docking techniques elucidate role programmed omics results indicate that significantly targets genes involved oxidative phosphorylation, mitophagy, dynamics, stress. Further findings confirmed Nrf-2/GPX4/xCT pathway serves as crucial target NSCLC. Knockdown Nrf-2 (si-Nrf-2) overexpression (ad-Nrf-2) were shown modulate therapeutic efficacy varying degrees. Additionally, modifications GPX4/xCT affected regulatory effects on autophagy, biogenesis, energy metabolism. These mechanisms may be mediated caspase ferroptosis-related signaling. Molecular biology experiments demonstrated intervention further inhibits phosphorylation FUNDC1 Tyr18 downregulates TOM20 expression. was found reduce expression PGC1α, Nrf-1, Tfam, resulting decrease respiration Overexpression counteract biogenesis. Confocal microscopy revealed increases fragmentation, subsequently inducing pathway-mediated death. However, genetic modification altered In conclusion, has been identified promising agent apoptosis ferroptosis represent key Targeting axis offers novel approach maintaining homeostasis within cellular microenvironment.

Language: Английский

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The role of mitochondrial dynamics in disease

MedComm, Journal Year: 2023, Volume and Issue: 4(6)

Published: Dec. 1, 2023

Mitochondria are multifaceted and dynamic organelles regulating various important cellular processes from signal transduction to determining cell fate. As properties of mitochondria, fusion fission accompanied with mitophagy, undergo constant changes in number morphology sustain mitochondrial homeostasis response context changes. Thus, the dysregulation dynamics mitophagy is unsurprisingly related diseases, but unclear underlying mechanism hinders their clinical application. In this review, we summarize recent developments molecular particularly different roles key components context. We also target treatment diseases cardiovascular system, nervous respiratory tumor metabolism demanding high-energy. these it common that excessive dominant by impaired mitophagy. But there have been many conflicting findings about them recently, which specifically highlighted view. look forward will help broaden our understanding be beneficial discovery novel selective therapeutic targets.

Language: Английский

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Mitochondrial membrane synthesis, remodelling and cellular trafficking

Journal of Inherited Metabolic Disease, Journal Year: 2024, Volume and Issue: 48(1)

Published: June 14, 2024

Abstract Mitochondria are dynamic cellular organelles with complex roles in metabolism and signalling. Primary mitochondrial disorders a group of approximately 400 monogenic arising from pathogenic genetic variants impacting structure, ultrastructure and/or function. Amongst these disorders, defects lipid biosynthesis, especially the unique membrane cardiolipin, biology an emerging characterised by clinical heterogeneity, but recurrent features including cardiomyopathy, encephalopathy, neurodegeneration, neuropathy 3‐methylglutaconic aciduria. This review discusses synthesis membrane, contact site cristae organising system (MICOS), dynamics trafficking, associated each processes. We highlight overlapping functions proteins involved biosynthesis protein import into mitochondria, pointing to overarching coordination synchronisation functions. also focuses on interactions between mitochondria other organelles, namely endoplasmic reticulum, peroxisomes, lysosomes droplets. signpost that may explain observation secondary dysfunction heterogeneous pathological Disruption organellar ultimately impairs homeostasis organismal health, highlighting central role human health disease.

Language: Английский

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Drp1 Proteins Released from Hydrolysis-driven Scaffold Disassembly Trigger Nucleotide-dependent Membrane Remodeling to Promote Scission

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Abstract Dynamin-related protein (Drp1) drives mitochondrial fission, dysregulation of which leads to neurodegenerative, metabolic, and apoptotic disorders. The precise mechanism fission completion is unclear. One prevailing model based on GTP-driven assembly Drp1 helices that increase confinement via force generation. However, constriction nanoscopic tubule radii appears necessary but not sufficient for scission. other disassembly a constricting scaffold membrane disturbance, the relation scission GTP hydrolysis remain uncertain. Elucidation complicated by multiple time-involved in dynamics mechanoenzyme activity, oligomer disassembly, remodeling. Using machine learning, synchrotron x-ray scattering, theoretical model, our data support where progressive enable free Drp1s their capacity inducing negative Gaussian curvature (NGC). Furthermore, we identify variants diminish this capacity. Machine learning reveals predicted NGC-generating sequences are contact with confined lipid tube, scission-enhancing remodeling triggered released upon disassembly. Teaser Free from oligomeric constrictase promotes GTP-hydrolysis dependent

Language: Английский

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Transcriptomic analysis of mitohormesis associated with lifespan extension inCaenorhabditis elegans

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 19, 2025

Abstract Non-lethal exposure to mitochondrial stress has been shown have beneficial effects due activation of signalling pathways, including the unfolded protein response (UPR mt ). Activation UPR restores function mitochondria and improves general health longevity in multiple model systems, termed mitohormesis. In C. elegans , mitohormesis can be accomplished by electron transport chain inhibition, decline translation, decreased import, numerous other methods that activate . However, not all promote longevity. These studies started question whether MT is directly correlated with Here, we attempt address this controversy unravelling complex molecular regulation nematode under different stressors induce performing RNA-sequencing profile transcriptome changes. Using comprehensive unbiased approach, aim determine specific transcriptomic changes reveal a correlation between Altogether study will provide mechanistic insights on how it correlates lifespan

Language: Английский

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Targeting Mitochondrial Dynamics during Lower-Limb Ischemia Reperfusion in Young and Old Mice: Effect of Mitochondrial Fission Inhibitor-1 (mDivi-1)

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 4025 - 4025

Published: April 4, 2024

Peripheral arterial disease (PAD) strikes more than 200 million people worldwide and has a severe prognosis by potentially leading to limb amputation and/or death, particularly in older patients. Skeletal muscle mitochondrial dysfunctions oxidative stress play major roles this relation with ischemia-reperfusion (IR) cycles. Mitochondrial dynamics through impairment of fission–fusion balance may contribute skeletal pathophysiology, but no data were reported the setting lower-limb IR despite need for new therapeutic options. We, therefore, investigated potential protective effect division inhibitor-1 (mDivi-1; 50 mg/kg) young (23 weeks) old (83 mice submitted two-hour ischemia followed reperfusion on systemic lactate, respiration calcium retention capacity, transcripts specific dynamics. At levels, an IR-related increase circulating lactate was still mDivi-1 use (+305.9% p < 0.0001, +269.4% 0.0001 mice, respectively). Further, IR-induced (more severely impaired (OXPHOS CI state, –68.2% −84.9% 23- 83-week mice) reduced capacity (–46.1% 0.001 −48.2% = 0.09, respectively) not corrected preconditioning, whatever age. treatment did oppose superoxide anion production (+71.4% +37.5% 0.05, transcript level, markers antioxidant enzymes (SOD 1, SOD 2, catalase, GPx) fission (Drp1, Fis) remained unchanged or tended be decreased ischemic leg. Fusion such as mitofusin 1 2 significantly after both groups. In conclusion, aging enhanced deleterious effects respiration, IR, failed protect mice.

Language: Английский

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Autophagy-targeting modulation to promote peripheral nerve regeneration

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(7), P. 1864 - 1882

Published: May 10, 2024

Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors intricate molecular mechanisms. Past studies have focused on that stimulate axonal outgrowth myelin regeneration. However, recent highlighted the pivotal role of autophagy in regeneration, particularly context injuries. Consequently, autophagy-targeting modulation has emerged as promising therapeutic approach to enhancing Our current understanding suggests activating facilitates rapid clearance damaged axons sheaths, thereby neuronal survival mitigating injury-induced oxidative stress inflammation. These actions collectively contribute creating favorable microenvironment for structural functional A range autophagy-inducing drugs interventions demonstrated beneficial effects alleviating neuropathy promoting preclinical models This review delves into regulation cell types involved summarizing potential can be harnessed promote this process. We hope our will offer novel insights perspectives exploitation pathways treatment neuropathies.

Language: Английский

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Targeting Mitochondria: Influence of Metabolites on Mitochondrial Heterogeneity

Cell Biochemistry and Function, Journal Year: 2024, Volume and Issue: 42(7)

Published: Oct. 1, 2024

ABSTRACT Mitochondria are vital organelles that provide energy for the metabolic processes of cells. These include regulating cellular metabolism, autophagy, apoptosis, calcium ions, and signaling processes. Despite their varying functions, mitochondria considered semi‐independent possess own genome, known as mtDNA, which encodes 13 proteins crucial oxidative phosphorylation. However, diversity reflects an organism's adaptation to physiological conditions plays a complex function in metabolism. Mitochondrial heterogeneity exists at single‐cell tissue levels, impacting cell shape, size, membrane potential, function. This can contribute progression diseases such neurodegenerative diseases, cancer. dynamics enhance stability cells sufficient requirement, but these activities not universal lead uneven mitochondria, resulting heterogeneity. Factors genetics, environmental compounds, pathways found affect Additionally, roles metabolites NADH ATP glycolysis's speed efficiency. An imbalance impair production redox potential mitochondria. Therefore, this review will explore influence shaping mitochondrial morphology, how changes age‐related therapeutic targets

Language: Английский

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Type 2 diabetes microenvironment promotes the development of Parkinson’s disease by activating microglial cell inflammation

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: July 10, 2024

Parkinson's disease (PD) is the second most common neurodegenerative in world, and type 2 diabetes (T2DM) PD are influenced by genetic environmental factors. Mitochondrial dysfunction inflammation pathogenic mechanisms of both diseases. However, close association between T2DM specific relationship them not yet clear. This study aimed to reveal connection two diseases establishing a mouse model comorbid T2DM, as well Bv2 cell model.

Language: Английский

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Oocyte quality is closely linked to DRP1 derived-mitochondrial fission and mitophagy by the NAD⁺ biosynthesis in a postovulatory-aging model of pigs

Journal of Animal Reproduciton and Biotechnology, Journal Year: 2024, Volume and Issue: 39(2), P. 67 - 80

Published: June 28, 2024

Background: Post-ovulatory aging (POA) of oocytes is related to a decrease in the quality and quantity caused by aging.Previous studies on characteristics POA have investigated injury early embryonic developmental ability, but no information available its effects mitochondrial fission mitophagy-related responses.In this study, we aimed elucidate molecular mechanisms underlying mitophagy vitro maturation (IVM) model based RNA sequencing analysis.Methods: The was obtained through an additional 24 h culture following IVM matured oocytes.NMN treatment administered at concentration 25 μM during oocyte process.We conducted MitoTracker staining Western blot experiments confirm changes function between groups.Additionally, comparative transcriptome analysis performed identify differentially expressed genes associated dynamics porcine oocytes.Results: In total, 32 common apoptosis 42 uniquely were detected (≥ 1.5-fold change) metaphase II oocytes, respectively.Functional analyses fission, oxidative stress, mitophagy, autophagy, cellular observed as major regulated biological processes for ability compared with model.Additionally, revealed that activation NAD + nicotinamide mononucleotide not only partly improved also model.Conclusions: summary, our data indicate play roles controlling oocytes.Additionally, found biosynthesis important pathway mediates DRP1-derived morphology, dynamic balance, model.

Language: Английский

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